Is CYP4V2 p.Leu499Phe (c.1495C>T) pathogenic?

CYP4V2 p.Leu499Phe (c.1495C>T) is classified Uncertain significance in CYP4V2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-24). AlphaMissense: ambiguous (0.5179); Very rare (popmax 0.00223%, eas).

How common is CYP4V2 p.Leu499Phe (c.1495C>T) in the general population?

CYP4V2 p.Leu499Phe (c.1495C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CYP4V2 p.Leu499Phe (c.1495C>T)?

AlphaMissense predicts ambiguous (score 0.5179) — an in-silico prediction, not a clinical call.

CYP4V2 p.Leu499Phe

c.1495C>T · rs761881255 · VCV1007391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.5179	ambiguous
REVEL	0.593	indeterminate
SaProt	LLR -12.96	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.64 · regional, not allelic
Overall
CADD	24.0	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 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,614,032 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
European (non-Finnish)	0.000763%	131,114

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.Leu499Phe
Coding: c.1495C>T
MANE Select: NM_207352
dbSNP: rs761881255
Type: single nucleotide variant
Location: chr4:186210558 (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-leu499phe (accessed [today's date]).

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