CYP27A1 P384L - GET-Evidence


CYP27A1 P384L

(CYP27A1 Pro384Leu)

Short summary

Probably not pathogenic. Although predicted to be disruptive and treated by some as pathogenic, reports of this variant in cases were all linked with an upstream frameshift variant — this supports the variant as a nonpathogenic ancestral polymorphism.

Variant evidence
Computational -1
Functional -
Case/Control 1

Present in a healthy PGP member. Reported cases had an upstream frameshift implying this variant was an ancestral polymorphism.

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Because it appears to have been ancestral to the pathogenic upstream frameshift mutation in the cases reported by Verrips et al, we are tentatively classifying this variant as benign.

Allele frequency

  • T @ chr2:219678877: 1.8% (191/10758) in EVS
  • T @ chr2:219387120: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.8% (191/10758)


Segev H, Reshef A, Clavey V, Delbart C, Routier G, Leitersdorf E. Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in a French family. Hum Genet. 1995 Feb;95(2):238-40. PubMed PMID: 7860076.

This paper reports the insertion of C causing frameshift and termination.

Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreƫls FJ, van Engelen BG, van den Heuvel LP. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000 May;123 ( Pt 5):908-19. PubMed PMID: 10775536.

32 families with cerebrotendinous xanthomatosis were examined for mutations in CYP27. This variant was seen in four families, but in all cases this was cis with a 5-6insC mutation previously reported as pathogenic (Segev et al.). Presumably that insertion was causal, not the substitution predicted for this downstream location (which would not have been transcribed). This variant may have been ancestral to the pathogenic insertion variant.

Prosser DE, Guo Y, Jia Z, Jones G. Structural motif-based homology modeling of CYP27A1 and site-directed mutational analyses affecting vitamin D hydroxylation. Biophys J. 2006 May 15;90(10):3389-409. Epub 2006 Feb 24. PubMed PMID: 16500955; PubMed Central PMCID: PMC1440725.

This paper studies the structure of the protein and attempts to explain why particular reported variants have pathogenic impact. It explains why this variant may have had a pathogenic impact, but appears to be unaware that all reported instances of the variant were coupled with the upstream frameshift mutation.


hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr2:219678877


Other external references

  • rs41272687
  • Score: 0.999 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 5

Edit history

Gene search

"GENE" or "GENE A123C":

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