Is ACOT2 p.Val346Met (c.1036G>A) pathogenic?

ACOT2 p.Val346Met (c.1036G>A) is classified Likely benign in ACOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: likely benign (0.0986); Ultra-rare (popmax 0.0125%, eas).

How common is ACOT2 p.Val346Met (c.1036G>A) in the general population?

ACOT2 p.Val346Met (c.1036G>A) is ultra-rare (popmax 0.0125%, eas) (gnomAD).

What do computational predictors say about ACOT2 p.Val346Met (c.1036G>A)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

ACOT2 p.Val346Met

c.1036G>A · VCV3261961

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.40	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 -9.3	GERP -4
Regional constraint	o/e 0.36	unconstrained · MANE · 252 bp · p 3.1e-11 · regional, not allelic
Overall
CADD	0.364	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 0.0125% East Asian · 5/40,122 alleles

Filtering AF 0.00486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00314%

Overall 0.000422% 6/1,421,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0125%	8,024
European (non-Finnish)	9.65e-05%	1,036,494

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: ACOT2
Protein: p.Val346Met
Coding: c.1036G>A
MANE Select: NM_006821
Type: single nucleotide variant
Location: chr14:73575097 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.22 · 1 PDB

Full ACOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT2 p.His328Arg Benign ★★ same type
ACOT2 p.Ala116Thr Uncertain significance ★ ⚠ same type
ACOT2 p.Ala145Val Uncertain significance ★ ⚠ same type
ACOT2 p.Ala304Val Uncertain significance ★ ⚠ same type
ACOT2 p.Ala452Thr Uncertain significance ★ ⚠ same type
ACOT2 p.Ala452Val Uncertain significance ★ ⚠ same type
ACOT2 p.Arg158Leu Uncertain significance ★ ⚠ same type
ACOT2 p.Arg16Gly Uncertain significance ★ ⚠ 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/acot2-p-val346met (accessed [today's date]).

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