Is ACOT8 p.Ser196Arg (c.588C>A) pathogenic?

ACOT8 p.Ser196Arg (c.588C>A) is classified Uncertain significance in ACOT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely benign (0.2539); Very rare (popmax 0.0022%, sas).

How common is ACOT8 p.Ser196Arg (c.588C>A) in the general population?

ACOT8 p.Ser196Arg (c.588C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ACOT8 p.Ser196Arg (c.588C>A)?

AlphaMissense predicts likely benign (score 0.2539) — an in-silico prediction, not a clinical call.

ACOT8 p.Ser196Arg

c.588C>A · VCV3824534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2539	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.72	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 1.4	GERP -1.5, phastCons 0.86
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	15.34	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000274% 4/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
European (non-Finnish)	0.000169%	590,019

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.Ser196Arg
Coding: c.588C>A
MANE Select: NM_005469
Type: single nucleotide variant
Location: chr20:45844321 (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-ser196arg (accessed [today's date]).

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