Is FA2H p.Pro274Thr (c.820C>A) pathogenic?

FA2H p.Pro274Thr (c.820C>A) is classified Uncertain significance in FA2H (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-18). AlphaMissense: ambiguous (0.4496); Very rare (popmax 0.00529%, amr); Associated with Inborn genetic diseases.

What condition is associated with FA2H p.Pro274Thr (c.820C>A)?

FA2H p.Pro274Thr (c.820C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FA2H p.Pro274Thr (c.820C>A) in the general population?

FA2H p.Pro274Thr (c.820C>A) is very rare (popmax 0.00529%, amr) (gnomAD).

What do computational predictors say about FA2H p.Pro274Thr (c.820C>A)?

AlphaMissense predicts ambiguous (score 0.4496) — an in-silico prediction, not a clinical call.

FA2H p.Pro274Thr

c.820C>A · rs373152103 · VCV2185693

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4496 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00529%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4496	ambiguous
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -11.57	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	29.4	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 0.00529% Admixed American · 3/56,710 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000689%

Overall 0.000376% 6/1,596,678 alleles · very rare exomes 5/1,444,660 · genomes 1/152,018 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00529%	18,903
South Asian	0.00112%	89,274
European (non-Finnish)	0.000171%	585,995

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.Pro274Thr
Coding: c.820C>A
MANE Select: NM_024306
dbSNP: rs373152103
Type: single nucleotide variant
Location: chr16:74716566 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 274: 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.Pro274Ala Uncertain significance ★★ ⚠ same residue
FA2H p.Pro274His Uncertain significance ★ ⚠ same residue
FAAH p.Glu274Gln Uncertain significance ★ ⚠ same residue
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

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-pro274thr (accessed [today's date]).

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