Is ACACB p.Ala2298Ser (c.6892G>T) pathogenic?

ACACB p.Ala2298Ser (c.6892G>T) is classified Uncertain significance in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely benign (0.1517); Very rare (popmax 6.84e-05%).

How common is ACACB p.Ala2298Ser (c.6892G>T) in the general population?

ACACB p.Ala2298Ser (c.6892G>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ACACB p.Ala2298Ser (c.6892G>T)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

ACACB p.Ala2298Ser

c.6892G>T · VCV3995961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -9.28	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 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 14 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	26.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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.Ala2298Ser
Coding: c.6892G>T
MANE Select: NM_001093
Type: single nucleotide variant
Location: chr12:109264336 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 2298: 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.Ala2298Thr 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-ala2298ser (accessed [today's date]).

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