Is ACACA p.Arg921Gln (c.2762G>A) pathogenic?

ACACA p.Arg921Gln (c.2762G>A) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-17). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.00446%, eas).

How common is ACACA p.Arg921Gln (c.2762G>A) in the general population?

ACACA p.Arg921Gln (c.2762G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ACACA p.Arg921Gln (c.2762G>A)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

ACACA p.Arg921Gln

c.2762G>A · rs770987352 · VCV2521465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -4.42	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 2.2	GERP -1.1, phastCons 0.96
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 4.1e-22 · regional, not allelic
Overall
CADD	22.8	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 R884Q vs ClinVar R921Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000889% 13/1,461,748 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
African / African-American	0.00267%	37,501
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)	0.000508%	196,668

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.Arg921Gln
Coding: c.2762G>A
MANE Select: NM_198834
dbSNP: rs770987352
Type: single nucleotide variant
Location: chr17:37243540 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 921: an α-helix

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

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ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
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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-arg921gln (accessed [today's date]).

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