Is ACAT1 p.Cys126Ser (c.377G>C) pathogenic?

ACAT1 p.Cys126Ser (c.377G>C) is classified Pathogenic/Likely pathogenic in ACAT1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-07-18). AlphaMissense: likely pathogenic (0.9494); Very rare (popmax 0.00267%, afr); Associated with beta-ketothiolase deficiency.

What condition is associated with ACAT1 p.Cys126Ser (c.377G>C)?

ACAT1 p.Cys126Ser (c.377G>C) is associated with beta-ketothiolase deficiency (ClinVar).

How common is ACAT1 p.Cys126Ser (c.377G>C) in the general population?

ACAT1 p.Cys126Ser (c.377G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Beta-ketothiolase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACAT1 p.Cys126Ser (c.377G>C)?

AlphaMissense predicts likely pathogenic (score 0.9494) — an in-silico prediction, not a clinical call.

ACAT1 p.Cys126Ser

c.377G>C · rs1278227329 · VCV666478

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-ketothiolase deficiency

Computational evidence

Protein change
AlphaMissense	0.9494	likely pathogenic ✓ concordant with ClinVar
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Overall
CADD	33.0	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 0.00267% African / African-American · 2/74,900 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000868% 14/1,613,778 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
African / African-Americangrpmax	0.00267%	37,450
European (non-Finnish)	0.000848%	117,989

Remaining individuals 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: ACAT1
Protein: p.Cys126Ser
Coding: c.377G>C
MANE Select: NM_003101 · reported on NM_000019
dbSNP: rs1278227329
Type: single nucleotide variant
Location: chr11:108135184 (GRCh38)
Structure: AlphaFold pLDDT 81.22 · 5 PDB
Residue 126: an α-helix

Full ACAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

beta-ketothiolase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Beta-ketothiolase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ACAT1 p.Cys126= Conflicting classifications of pathogenicity ★ same residue
ACAT1 c.1006-1G>A Pathogenic ★★ same condition
ACAT1 c.1006-1G>C Pathogenic ★★ same condition
ACAT1 c.1006-2A>C Pathogenic ★★ same condition
ACAT1 c.1163+2T>C Pathogenic ★★ same condition
ACAT1 c.120+1G>C Likely pathogenic ★★ same condition
ACAT1 c.121-3C>G Pathogenic/Likely pathogenic ★★ same condition
ACAT1 c.238+2T>A Pathogenic/Likely pathogenic ★★ same condition

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/acat1-p-cys126ser (accessed [today's date]).

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