Is ACACB p.Pro361Leu (c.1082C>T) pathogenic?

ACACB p.Pro361Leu (c.1082C>T) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-21). AlphaMissense: likely pathogenic (0.705); Ultra-rare (popmax 0.0468%, eas).

How common is ACACB p.Pro361Leu (c.1082C>T) in the general population?

ACACB p.Pro361Leu (c.1082C>T) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about ACACB p.Pro361Leu (c.1082C>T)?

AlphaMissense predicts likely pathogenic (score 0.705) — an in-silico prediction, not a clinical call.

ACACB p.Pro361Leu

c.1082C>T · rs199655635 · VCV2471274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.705	likely pathogenic
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -14.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0468% East Asian · 21/44,888 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00657% 106/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,138
European (non-Finnish)	0.00661%	15,129
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.00267%	37,455
Admixed American	0.00167%	59,998

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.Pro361Leu
Coding: c.1082C>T
MANE Select: NM_001093
dbSNP: rs199655635
Type: single nucleotide variant
Location: chr12:109172321 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 361: 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-pro361leu (accessed [today's date]).

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