Is ACACB p.Arg710Gln (c.2129G>A) pathogenic?

ACACB p.Arg710Gln (c.2129G>A) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.8574); Very rare (popmax 0.00225%, eas).

How common is ACACB p.Arg710Gln (c.2129G>A) in the general population?

ACACB p.Arg710Gln (c.2129G>A) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about ACACB p.Arg710Gln (c.2129G>A)?

AlphaMissense predicts likely pathogenic (score 0.8574) — an in-silico prediction, not a clinical call.

ACACB p.Arg710Gln

c.2129G>A · rs1225546821 · VCV2556575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8574	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,478 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000499% 8/1,602,002 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,478
Remaining individualsnot grpmax-eligible	0.00162%	61,874
South Asian	0.0011%	90,762
European (non-Finnish)	0.000427%	234,053

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.Arg710Gln
Coding: c.2129G>A
MANE Select: NM_001093
dbSNP: rs1225546821
Type: single nucleotide variant
Location: chr12:109188147 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 710: an α-helix; the biotin carboxylation domain

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

Similar variants

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
ACACB p.Gln1257Glu 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-arg710gln (accessed [today's date]).

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