Is ACACA p.Met181Leu (c.541A>T) pathogenic?

ACACA p.Met181Leu (c.541A>T) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-01). AlphaMissense: likely pathogenic (0.5992); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with ACACA p.Met181Leu (c.541A>T)?

ACACA p.Met181Leu (c.541A>T) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is ACACA p.Met181Leu (c.541A>T) in the general population?

ACACA p.Met181Leu (c.541A>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

What do computational predictors say about ACACA p.Met181Leu (c.541A>T)?

AlphaMissense predicts likely pathogenic (score 0.5992) — an in-silico prediction, not a clinical call.

ACACA p.Met181Leu

c.541A>T · rs2146590612 · VCV981841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.5992	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 1,637 bp · p 5.4e-08 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M144L vs ClinVar M181L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACACA
Protein: p.Met181Leu
Coding: c.541A>T
MANE Select: NM_198834
dbSNP: rs2146590612
Type: single nucleotide variant
Location: chr17:37283336 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 144 UniProt numbering: the biotin carboxylation domain; an α-helix

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

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same type
ACACA p.Arg1206His Uncertain significance ★★ ⚠ same type
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same type
ACACA p.Arg745Trp Uncertain significance ★★ ⚠ same type
ACACA p.Asn1903Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn950Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asp2228Asn 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/acaca-p-met181leu (accessed [today's date]).

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