Is ACOT4 p.Gln324Pro (c.971A>C) pathogenic?

ACOT4 p.Gln324Pro (c.971A>C) is classified Uncertain significance in ACOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.4582); Very rare (popmax 0.00288%, nfe).

How common is ACOT4 p.Gln324Pro (c.971A>C) in the general population?

ACOT4 p.Gln324Pro (c.971A>C) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about ACOT4 p.Gln324Pro (c.971A>C)?

AlphaMissense predicts ambiguous (score 0.4582) — an in-silico prediction, not a clinical call.

ACOT4 p.Gln324Pro

c.971A>C · VCV4636819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4582	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -13.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.97	GERP 0.57, phastCons 0.022
Regional constraint	o/e 1.03	unconstrained · MANE · 3,691 bp · p 0.48 · regional, not allelic
Overall
CADD	22.7	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 0.00288% European (non-Finnish) · 34/1,180,046 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00239% 35/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,707
African / African-American	0.00133%	75,076

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: ACOT4
Protein: p.Gln324Pro
Coding: c.971A>C
MANE Select: NM_152331
Type: single nucleotide variant
Location: chr14:73595359 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.47 · 1 PDB

Full ACOT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT4 p.Ala235Gly Uncertain significance ★ ⚠ same type
ACOT4 p.Ala235Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala242Ser Uncertain significance ★ ⚠ same type
ACOT4 p.Ala242Val Uncertain significance ★ ⚠ same type
ACOT4 p.Ala372Gly Uncertain significance ★ ⚠ same type
ACOT4 p.Ala48Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala65Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala65Val 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/acot4-p-gln324pro (accessed [today's date]).

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