Is FA2H p.Val124Ala (c.371T>C) pathogenic?

FA2H p.Val124Ala (c.371T>C) is classified Likely pathogenic in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-02). AlphaMissense: likely pathogenic (0.6352); Very rare (popmax 0.00136%, nfe); Associated with FA2H-related disorder.

What condition is associated with FA2H p.Val124Ala (c.371T>C)?

FA2H p.Val124Ala (c.371T>C) is associated with FA2H-related disorder (ClinVar).

How common is FA2H p.Val124Ala (c.371T>C) in the general population?

FA2H p.Val124Ala (c.371T>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about FA2H p.Val124Ala (c.371T>C)?

AlphaMissense predicts likely pathogenic (score 0.6352) — an in-silico prediction, not a clinical call.

FA2H p.Val124Ala

c.371T>C · VCV4931253

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FA2H-related disorder

Computational evidence

Protein change
AlphaMissense	0.6352	likely pathogenic ✓ concordant with ClinVar
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -10.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	27.8	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 0.00136% European (non-Finnish) · 16/1,180,042 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000991% 16/1,614,232 alleles · very rare exomes 16/1,461,874 · genomes 0/152,358 · joint denominator

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.Val124Ala
Coding: c.371T>C
MANE Select: NM_024306
Type: single nucleotide variant
Location: chr16:74727379 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53

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

Disease context

FA2H-related disorder

Similar variants

FA2H p.Pro148Leu Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Thr207Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
FA2H p.Arg154Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
FA2H c.-1C>A Likely benign same condition
FA2H p.Ser322= Likely benign same condition
FAAH c.1357-5C>T Benign same condition
FAAH p.Pro163= Likely benign same condition
FA2H p.Met220fs 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/fa2h-p-val124ala (accessed [today's date]).

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