Is ACACA p.Arg303His (c.908G>A) pathogenic?

ACACA p.Arg303His (c.908G>A) is classified Conflicting classifications of pathogenicity in ACACA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0744); Rare (popmax 0.352%, afr).

How common is ACACA p.Arg303His (c.908G>A) in the general population?

ACACA p.Arg303His (c.908G>A) is rare (popmax 0.352%, afr) (gnomAD).

What do computational predictors say about ACACA p.Arg303His (c.908G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

ACACA p.Arg303His

c.908G>A · rs73982299 · VCV1629279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.352%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -8.15	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 1.4	GERP -1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,780 bp · p 0.26 · regional, not allelic
Overall
CADD	24.2	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 R266H vs ClinVar R303H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.352% African / African-American · 264/75,032 alleles

Filtering AF 0.317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.303%

Overall 0.0174% 281/1,613,466 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.352%	284
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed American	0.00833%	12,005
South Asian	0.0022%	45,527
European (non-Finnish)	0.000339%	294,850

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.Arg303His
Coding: c.908G>A
MANE Select: NM_198834
dbSNP: rs73982299
Type: single nucleotide variant
Location: chr17:37274293 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 303: the biotin carboxylation domain; an α-helix; the atp-grasp domain

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

Similar variants

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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-arg303his (accessed [today's date]).

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