Is FA2H p.Val255Ile (c.763G>A) pathogenic?

FA2H p.Val255Ile (c.763G>A) is classified Conflicting classifications of pathogenicity in FA2H (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-05). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with FA2H p.Val255Ile (c.763G>A)?

FA2H p.Val255Ile (c.763G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FA2H p.Val255Ile (c.763G>A) in the general population?

FA2H p.Val255Ile (c.763G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about FA2H p.Val255Ile (c.763G>A)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

FA2H p.Val255Ile

c.763G>A · rs773459488 · VCV1509337

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -4.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.6
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	11.06	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 0.004% African / African-American · 3/74,942 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00124% 20/1,613,808 alleles · very rare exomes 18/1,461,588 · genomes 2/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,981
Admixed American	0.00333%	30,006
European (non-Finnish)	0.00119%	84,289
South Asian	0.0011%	91,094

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: FA2H
Protein: p.Val255Ile
Coding: c.763G>A
MANE Select: NM_024306
dbSNP: rs773459488
Type: single nucleotide variant
Location: chr16:74719011 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 255: the fatty acid hydroxylase domain

Full FA2H gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FA2H p.Arg189Ter Pathogenic ★★ same condition
FA2H c.363+5C>A Uncertain significance ★★ same condition
FA2H p.Arg151Gly Uncertain significance ★★ ⚠ same condition
FA2H p.Arg28Cys Uncertain significance ★★ ⚠ same condition
FA2H p.Gln289His Uncertain significance ★★ ⚠ same condition
FA2H p.Gln344Glu Uncertain significance ★★ ⚠ same condition
FA2H p.Gln344His Uncertain significance ★★ ⚠ same condition
FA2H p.Gly23Arg Uncertain significance ★★ ⚠ 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/fa2h-p-val255ile (accessed [today's date]).

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