Is CYP4V2 p.His331Pro (c.992A>C) pathogenic?

CYP4V2 p.His331Pro (c.992A>C) is classified Pathogenic/Likely pathogenic in CYP4V2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.9719); Ultra-rare (popmax 0.0468%, eas); Associated with CYP4V2-related disorder.

What condition is associated with CYP4V2 p.His331Pro (c.992A>C)?

CYP4V2 p.His331Pro (c.992A>C) is associated with CYP4V2-related disorder, Bietti crystalline corneoretinal dystrophy (ClinVar).

How common is CYP4V2 p.His331Pro (c.992A>C) in the general population?

CYP4V2 p.His331Pro (c.992A>C) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about CYP4V2 p.His331Pro (c.992A>C)?

AlphaMissense predicts likely pathogenic (score 0.9719) — an in-silico prediction, not a clinical call.

CYP4V2 p.His331Pro

c.992A>C · rs199476197 · VCV39275

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CYP4V2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9719	likely pathogenic ✓ concordant with ClinVar · top 9% in CYP4V2
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -16.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.64 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,902 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0013% 21/1,614,076 alleles · ultra-rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CYP4V2
Protein: p.His331Pro
Coding: c.992A>C
MANE Select: NM_207352
dbSNP: rs199476197
Type: single nucleotide variant
Location: chr4:186205204 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.05
Residue 331: a UniProt-annotated variant site (in bcd; impaired omega hydroxylase activity)

Full CYP4V2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CYP4V2-related disorder

Also linked: Bietti crystalline corneoretinal dystrophy

Similar variants

CYP4V2 p.His331= Likely benign ★ same residue
CYP4V2 c.1091-2A>G Pathogenic/Likely pathogenic ★★ same condition
CYP4V2 c.413+1G>A Likely pathogenic ★★ same condition
CYP4V2 c.414-1G>A Pathogenic/Likely pathogenic ★★ same condition
CYP4V2 c.801+1G>A Pathogenic ★★ same condition
CYP4V2 p.Arg232Ter Pathogenic ★★ same condition
CYP4V2 p.Arg390Cys Pathogenic ★★ same condition
CYP4V2 p.Arg390His Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cyp4v2-p-his331pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown