Is CYP4V2 p.Ser366Pro (c.1096T>C) pathogenic?

CYP4V2 p.Ser366Pro (c.1096T>C) is classified Uncertain significance in CYP4V2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-27). AlphaMissense: ambiguous (0.3697); Very rare (popmax 0.000339%, nfe).

How common is CYP4V2 p.Ser366Pro (c.1096T>C) in the general population?

CYP4V2 p.Ser366Pro (c.1096T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CYP4V2 p.Ser366Pro (c.1096T>C)?

AlphaMissense predicts ambiguous (score 0.3697) — an in-silico prediction, not a clinical call.

CYP4V2 p.Ser366Pro

c.1096T>C · rs200636986 · VCV1945456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3697	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -16.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.64 · regional, not allelic
Overall
CADD	23.2	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 0.000339% European (non-Finnish) · 4/1,180,026 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,088 alleles · very 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.Ser366Pro
Coding: c.1096T>C
MANE Select: NM_207352
dbSNP: rs200636986
Type: single nucleotide variant
Location: chr4:186208870 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.05

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

Similar variants

CYP4V2 c.1091-2A>G Pathogenic/Likely pathogenic ★★ same type
CYP4V2 c.413+1G>A Likely pathogenic ★★ same type
CYP4V2 c.414-1G>A Pathogenic/Likely pathogenic ★★ same type
CYP4V2 c.801+1G>A Pathogenic ★★ same type
CYP4V2 p.Arg232Ter Pathogenic ★★ same type
CYP4V2 p.Arg390Cys Pathogenic ★★ same type
CYP4V2 p.Arg390His Pathogenic/Likely pathogenic ★★ same type
CYP4V2 p.Arg390Leu Likely pathogenic ★★ same type

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-ser366pro (accessed [today's date]).

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