Is ACACA p.Asn2271Ser (c.6812A>G) pathogenic?

ACACA p.Asn2271Ser (c.6812A>G) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely benign (0.0556); Very rare (popmax 0.00534%, nfe).

How common is ACACA p.Asn2271Ser (c.6812A>G) in the general population?

ACACA p.Asn2271Ser (c.6812A>G) is very rare (popmax 0.00534%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Asn2271Ser (c.6812A>G)?

AlphaMissense predicts likely benign (score 0.0556) — an in-silico prediction, not a clinical call.

ACACA p.Asn2271Ser

c.6812A>G · rs139634742 · VCV2343742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0556	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.47	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 2.1	GERP -1.1, phastCons 0.99
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	14.96	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM N2234S vs ClinVar N2271S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% European (non-Finnish) · 63/1,180,042 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00428% 69/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00534%	18,731
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,455
East Asian	0.00223%	44,882
Finnishnot grpmax-eligible	0.00156%	64,010

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: ACACA
Protein: p.Asn2271Ser
Coding: c.6812A>G
MANE Select: NM_198834
dbSNP: rs139634742
Type: single nucleotide variant
Location: chr17:37097075 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2271: an α-helix; a UniProt-annotated variant site (frequency <0.004; may play a role in breast cancer susceptibility)

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

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-asn2271ser (accessed [today's date]).

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