Is ACACB p.Ala346= (c.1038G>A) pathogenic?

ACACB p.Ala346= (c.1038G>A) is classified Likely benign in ACACB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-07). Ultra-rare (popmax 0.0134%, eas); Associated with ACACB-related disorder.

What condition is associated with ACACB p.Ala346= (c.1038G>A)?

ACACB p.Ala346= (c.1038G>A) is associated with ACACB-related disorder (ClinVar).

How common is ACACB p.Ala346= (c.1038G>A) in the general population?

ACACB p.Ala346= (c.1038G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

ACACB p.Ala346=

c.1038G>A · rs575445770 · VCV3032646

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

ACACB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.6	GERP -4.2
Overall
CADD	12.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,874 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00223% 36/1,613,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,479
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.0022%	45,528
European (non-Finnish)	0.00203%	49,166
Finnishnot grpmax-eligible	0.00156%	64,032

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.Ala346=
Coding: c.1038G>A
MANE Select: NM_001093
dbSNP: rs575445770
Type: single nucleotide variant
Location: chr12:109172277 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 346: the biotin carboxylation domain; a β-strand

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

Disease context

ACACB-related disorder

Similar variants

ACACB p.Ala346Glu Uncertain significance ★ ⚠ same residue
ACACB p.Arg939Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
ACACB p.Phe578Leu Uncertain significance ★ ⚠ same condition
ACACB p.Ser1199= Conflicting classifications of pathogenicity ★ same condition
ACACB p.Glu1608Lys Uncertain significance ⚠ same condition
ACACB p.Met1253Thr Uncertain significance ⚠ same condition
ACACB p.Met2164Thr Uncertain significance ⚠ same condition
ACACB c.1117+3A>G Likely benign same condition

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-ala346 (accessed [today's date]).

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