Is ACOT8 p.Pro90Ser (c.268C>T) pathogenic?

ACOT8 p.Pro90Ser (c.268C>T) is classified Uncertain significance in ACOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). AlphaMissense: ambiguous (0.3619); Very rare (popmax 0.00169%, amr).

How common is ACOT8 p.Pro90Ser (c.268C>T) in the general population?

ACOT8 p.Pro90Ser (c.268C>T) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about ACOT8 p.Pro90Ser (c.268C>T)?

AlphaMissense predicts ambiguous (score 0.3619) — an in-silico prediction, not a clinical call.

ACOT8 p.Pro90Ser

c.268C>T · rs201318577 · VCV2515541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Computational evidence

Protein change
AlphaMissense	0.3619	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -4.10	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	26.6	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 0.00169% Admixed American · 1/59,284 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000314%

Overall 0.00586% 94/1,605,002 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.255%	392
Remaining individualsnot grpmax-eligible	0.0129%	7,764
Admixed Americangrpmax	0.00169%	59,284
European (non-Finnish)	0.000851%	117,502

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro90Ser
Coding: c.268C>T
MANE Select: NM_005469
dbSNP: rs201318577
Type: single nucleotide variant
Location: chr20:45848670 (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-pro90ser (accessed [today's date]).

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