Is ACOT9 p.Arg343Pro (c.1028G>C) pathogenic?

ACOT9 p.Arg343Pro (c.1028G>C) is classified Uncertain significance in ACOT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.5792); Ultra-rare (popmax 0.0109%, amr).

How common is ACOT9 p.Arg343Pro (c.1028G>C) in the general population?

ACOT9 p.Arg343Pro (c.1028G>C) is ultra-rare (popmax 0.0109%, amr) (gnomAD).

What do computational predictors say about ACOT9 p.Arg343Pro (c.1028G>C)?

AlphaMissense predicts likely pathogenic (score 0.5792) — an in-silico prediction, not a clinical call.

ACOT9 p.Arg343Pro

c.1028G>C · VCV3824555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5792	likely pathogenic
REVEL	0.456	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.094 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R334P vs ClinVar R343P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% Admixed American · 5/45,774 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00271%

Overall 0.000456% 5/1,096,288 alleles · ultra-rare

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: ACOT9
Protein: p.Arg343Pro
Coding: c.1028G>C
MANE Select: NM_001037171
Type: single nucleotide variant
Location: chrX:23705072 (GRCh38)
Structure: AlphaFold pLDDT 85.31
Residue 343: the hotdog acot-type 2 domain

Full ACOT9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT9 p.Ala438Val Likely benign ★★ same type
ACOT9 p.His198Arg Likely benign ★★ same type
ACOT9 p.Ala146Pro Uncertain significance ★ ⚠ same type
ACOT9 p.Arg110Gln Uncertain significance ★ ⚠ same type
ACOT9 p.Arg215Cys Uncertain significance ★ ⚠ same type
ACOT9 p.Arg286Trp Uncertain significance ★ ⚠ same type
ACOT9 p.Arg313Trp Uncertain significance ★ ⚠ same type
ACOT9 p.Arg429Trp 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/acot9-p-arg343pro (accessed [today's date]).

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