Is ACOT2 p.Ala145Val (c.434C>T) pathogenic?

ACOT2 p.Ala145Val (c.434C>T) is classified Uncertain significance in ACOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.4879); Absent from gnomAD v4.1.

How common is ACOT2 p.Ala145Val (c.434C>T) in the general population?

ACOT2 p.Ala145Val (c.434C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACOT2 p.Ala145Val (c.434C>T)?

AlphaMissense predicts ambiguous (score 0.4879) — an in-silico prediction, not a clinical call.

ACOT2 p.Ala145Val

c.434C>T · VCV3999036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4879 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4879	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -11.66	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.5, phastCons 0.93
Regional constraint	o/e 1.01	unconstrained · MANE · 5,688 bp · p 0.82 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACOT2
Protein: p.Ala145Val
Coding: c.434C>T
MANE Select: NM_006821
Type: single nucleotide variant
Location: chr14:73569674 (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.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
ACOT2 p.Arg180Gln 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-ala145val (accessed [today's date]).

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