Is ACOT12 p.His342Pro (c.1025A>C) pathogenic?

ACOT12 p.His342Pro (c.1025A>C) is classified Uncertain significance in ACOT12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-17). AlphaMissense: likely benign (0.0612); Very rare (popmax 0.00441%, nfe).

How common is ACOT12 p.His342Pro (c.1025A>C) in the general population?

ACOT12 p.His342Pro (c.1025A>C) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about ACOT12 p.His342Pro (c.1025A>C)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

ACOT12 p.His342Pro

c.1025A>C · VCV3481292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -4.10	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 0.46	GERP 0.32, phastCons 0.26
Regional constraint	o/e 1.04	unconstrained · MANE · 64 kb · p 0.33 · regional, not allelic
Overall
CADD	13.89	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 0.00441% European (non-Finnish) · 52/1,179,898 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00341% 55/1,613,478 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,690
Admixed American	0.00167%	59,872
Remaining individualsnot grpmax-eligible	0.0016%	62,474
Finnishnot grpmax-eligible	0.00156%	64,028

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: ACOT12
Protein: p.His342Pro
Coding: c.1025A>C
MANE Select: NM_130767
Type: single nucleotide variant
Location: chr5:81343837 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 3 PDB
Residue 342: the start domain

Full ACOT12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT12 c.1518+1G>A Uncertain significance ★ same type
ACOT12 p.Ala107Val Uncertain significance ★ ⚠ same type
ACOT12 p.Ala113Pro Uncertain significance ★ ⚠ same type
ACOT12 p.Ala213Asp Uncertain significance ★ ⚠ same type
ACOT12 p.Ala274Gly Uncertain significance ★ ⚠ same type
ACOT12 p.Ala290Thr Uncertain significance ★ ⚠ same type
ACOT12 p.Ala358Ser Uncertain significance ★ ⚠ same type
ACOT12 p.Ala536Ser 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/acot12-p-his342pro (accessed [today's date]).

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