Is ACOT8 p.Ser111Phe (c.332C>T) pathogenic?

ACOT8 p.Ser111Phe (c.332C>T) is classified Uncertain significance in ACOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4839); Very rare (popmax 0.00133%, afr).

How common is ACOT8 p.Ser111Phe (c.332C>T) in the general population?

ACOT8 p.Ser111Phe (c.332C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACOT8 p.Ser111Phe (c.332C>T)?

AlphaMissense predicts ambiguous (score 0.4839) — an in-silico prediction, not a clinical call.

ACOT8 p.Ser111Phe

c.332C>T · VCV3999184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4839	ambiguous
REVEL	0.227	benign-leaning
SaProt	LLR -9.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,036 alleles

Overall 6.84e-05% 1/1,461,682 alleles · very 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: ACOT8
Protein: p.Ser111Phe
Coding: c.332C>T
MANE Select: NM_005469
Type: single nucleotide variant
Location: chr20:45848606 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.58

Full ACOT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT8 p.Ala263Thr Uncertain significance ★ ⚠ same type
ACOT8 p.Ala267Gly Uncertain significance ★ ⚠ same type
ACOT8 p.Ala267Val Uncertain significance ★ ⚠ same type
ACOT8 p.Ala280Asp Uncertain significance ★ ⚠ same type
ACOT8 p.Arg100Gln Uncertain significance ★ ⚠ same type
ACOT8 p.Arg102Gln Uncertain significance ★ ⚠ same type
ACOT8 p.Arg110His Uncertain significance ★ ⚠ same type
ACOT8 p.Arg177Gln 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/acot8-p-ser111phe (accessed [today's date]).

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