Is ACOT2 p.Pro214Gln (c.641C>A) pathogenic?

ACOT2 p.Pro214Gln (c.641C>A) is classified Uncertain significance in ACOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1246); Ultra-rare (popmax 0.022%, amr).

How common is ACOT2 p.Pro214Gln (c.641C>A) in the general population?

ACOT2 p.Pro214Gln (c.641C>A) is ultra-rare (popmax 0.022%, amr) (gnomAD).

What do computational predictors say about ACOT2 p.Pro214Gln (c.641C>A)?

AlphaMissense predicts likely benign (score 0.1246) — an in-silico prediction, not a clinical call.

ACOT2 p.Pro214Gln

c.641C>A · VCV3998965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1246 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1246	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -3.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 2, phastCons 0.91
Regional constraint	o/e 1.01	unconstrained · MANE · 5,688 bp · p 0.82 · regional, not allelic
Overall
CADD	22.4	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 0.022% Admixed American · 13/59,158 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.0048% 77/1,603,288 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.022%	4,551
Middle Eastern	0.0167%	5,986
African / African-American	0.0148%	6,778
Remaining individualsnot grpmax-eligible	0.0129%	7,747
European (non-Finnish)	0.00374%	26,719

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: ACOT2
Protein: p.Pro214Gln
Coding: c.641C>A
MANE Select: NM_006821
Type: single nucleotide variant
Location: chr14:73569881 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.22 · 1 PDB
Residue 214: a β-strand

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.Ala145Val 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

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-pro214gln (accessed [today's date]).

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