Is ACACB p.Cys365Phe (c.1094G>T) pathogenic?

ACACB p.Cys365Phe (c.1094G>T) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00364%, nfe).

How common is ACACB p.Cys365Phe (c.1094G>T) in the general population?

ACACB p.Cys365Phe (c.1094G>T) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about ACACB p.Cys365Phe (c.1094G>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

ACACB p.Cys365Phe

c.1094G>T · rs769036400 · VCV2569878

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -4.2
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	15.26	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 0.00364% European (non-Finnish) · 43/1,180,028 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00308% 45/1,461,844 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,443
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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: ACACB
Protein: p.Cys365Phe
Coding: c.1094G>T
MANE Select: NM_001093
dbSNP: rs769036400
Type: single nucleotide variant
Location: chr12:109172333 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 365: the biotin carboxylation domain; an α-helix

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

Similar variants

ACACB p.Val958Met Uncertain significance ★★ ⚠ same type
ACACB c.6942+9C>T Benign ★★ same type
ACACB c.6943-8G>A Benign ★★ same type
ACACB c.7113+7C>T Benign/Likely benign ★★ same type
ACACB p.Ala650= Likely benign ★★ same type
ACACB p.Arg1786Gln Likely benign ★★ ⚠ same type
ACACB p.Asp1481Val Benign/Likely benign ★★ ⚠ same type
ACACB p.Gln1257Glu Benign ★★ 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/acacb-p-cys365phe (accessed [today's date]).

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