Is ACOT2 p.Val85Met (c.253G>A) pathogenic?

ACOT2 p.Val85Met (c.253G>A) is classified Uncertain significance in ACOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: ambiguous (0.4382); Ultra-rare (popmax 0.0462%, sas).

How common is ACOT2 p.Val85Met (c.253G>A) in the general population?

ACOT2 p.Val85Met (c.253G>A) is ultra-rare (popmax 0.0462%, sas) (gnomAD).

What do computational predictors say about ACOT2 p.Val85Met (c.253G>A)?

AlphaMissense predicts ambiguous (score 0.4382) — an in-silico prediction, not a clinical call.

ACOT2 p.Val85Met

c.253G>A · VCV3998957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4382 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0462%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4382	ambiguous
REVEL	0.718	pathogenic-leaning
SaProt	LLR -11.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 5,688 bp · p 0.82 · regional, not allelic
Overall
CADD	25.1	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 0.0462% South Asian · 42/90,980 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00323% 52/1,611,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0462%	2,166
Middle Eastern	0.0193%	5,172
Remaining individualsnot grpmax-eligible	0.00481%	20,776
European (non-Finnish)	0.000509%	196,571

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.Val85Met
Coding: c.253G>A
MANE Select: NM_006821
Type: single nucleotide variant
Location: chr14:73569493 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.22 · 1 PDB
Residue 85: a β-strand

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

Similar variants

ACOT2 p.Val85Gly Uncertain significance ★ ⚠ same residue
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

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-val85met (accessed [today's date]).

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