Is ACOT9 p.Ala146Pro (c.436G>C) pathogenic?

ACOT9 p.Ala146Pro (c.436G>C) is classified Uncertain significance in ACOT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.1003); Ultra-rare (popmax 0.0131%, nfe).

How common is ACOT9 p.Ala146Pro (c.436G>C) in the general population?

ACOT9 p.Ala146Pro (c.436G>C) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about ACOT9 p.Ala146Pro (c.436G>C)?

AlphaMissense predicts likely benign (score 0.1003) — an in-silico prediction, not a clinical call.

ACOT9 p.Ala146Pro

c.436G>C · VCV4636842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1003 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1003	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -3.6	GERP -3.8
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.094 · regional, not allelic
Overall
CADD	0.972	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A137P vs ClinVar A146P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0131% European (non-Finnish) · 117/890,110 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.0101% 122/1,202,661 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,608
Remaining individualsnot grpmax-eligible	0.00634%	15,773
African / African-American	0.00351%	28,452

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.Ala146Pro
Coding: c.436G>C
MANE Select: NM_001037171
Type: single nucleotide variant
Location: chrX:23722718 (GRCh38)
Structure: AlphaFold pLDDT 85.31
Residue 146: the hotdog acot-type 1 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.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.Arg343Pro 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-ala146pro (accessed [today's date]).

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