Is ACOT4 p.Arg389Ser (c.1167G>C) pathogenic?

ACOT4 p.Arg389Ser (c.1167G>C) is classified Uncertain significance in ACOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: likely benign (0.3135); Ultra-rare (popmax 0.0314%, eas).

How common is ACOT4 p.Arg389Ser (c.1167G>C) in the general population?

ACOT4 p.Arg389Ser (c.1167G>C) is ultra-rare (popmax 0.0314%, eas) (gnomAD).

What do computational predictors say about ACOT4 p.Arg389Ser (c.1167G>C)?

AlphaMissense predicts likely benign (score 0.3135) — an in-silico prediction, not a clinical call.

ACOT4 p.Arg389Ser

c.1167G>C · rs374310894 · VCV2602177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0314%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3135	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.78	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 0.58	GERP -1.4, phastCons 0.055
Regional constraint	o/e 1.03	unconstrained · MANE · 3,691 bp · p 0.48 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0314% East Asian · 14/44,580 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.00131% 21/1,603,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0314%	3,184
Remaining individualsnot grpmax-eligible	0.00807%	12,390
South Asian	0.0022%	45,382

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.Arg389Ser
Coding: c.1167G>C
MANE Select: NM_152331
dbSNP: rs374310894
Type: single nucleotide variant
Location: chr14:73595555 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.47 · 1 PDB
Residue 389: an α-helix

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-arg389ser (accessed [today's date]).

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