Is ACOT2 p.Ser133Ile (c.398G>T) pathogenic?

ACOT2 p.Ser133Ile (c.398G>T) is classified Uncertain significance in ACOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: likely pathogenic (0.6914); Absent from gnomAD v4.1.

How common is ACOT2 p.Ser133Ile (c.398G>T) in the general population?

ACOT2 p.Ser133Ile (c.398G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACOT2 p.Ser133Ile (c.398G>T)?

AlphaMissense predicts likely pathogenic (score 0.6914) — an in-silico prediction, not a clinical call.

ACOT2 p.Ser133Ile

c.398G>T · rs759855280 · VCV2335547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6914 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,602,964)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6914	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -12.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 5,688 bp · p 0.82 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,602,964). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACOT2
Protein: p.Ser133Ile
Coding: c.398G>T
MANE Select: NM_006821
dbSNP: rs759855280
Type: single nucleotide variant
Location: chr14:73569638 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.22 · 1 PDB
Residue 133: a β-strand

Full ACOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT2 p.Ser133Arg Uncertain significance ★ ⚠ same residue
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

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-ser133ile (accessed [today's date]).

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