Is ACACB p.Arg2282His (c.6845G>A) pathogenic?

ACACB p.Arg2282His (c.6845G>A) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.2906); Rare (popmax 0.114%, eas).

How common is ACACB p.Arg2282His (c.6845G>A) in the general population?

ACACB p.Arg2282His (c.6845G>A) is rare (popmax 0.114%, eas) (gnomAD).

What do computational predictors say about ACACB p.Arg2282His (c.6845G>A)?

AlphaMissense predicts likely benign (score 0.2906) — an in-silico prediction, not a clinical call.

ACACB p.Arg2282His

c.6845G>A · VCV3995690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2906 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2906	likely benign
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 14 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.114% East Asian · 51/44,880 alleles

Filtering AF 0.0887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0799%

Overall 0.00347% 56/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.114%	880
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,340

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.Arg2282His
Coding: c.6845G>A
MANE Select: NM_001093
Type: single nucleotide variant
Location: chr12:109264289 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 2282: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

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

Similar variants

ACACB p.Arg2282Cys Uncertain significance ★ ⚠ same residue
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

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-arg2282his (accessed [today's date]).

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