Is ACACB p.Arg939Ser (c.2817A>T) pathogenic?

ACACB p.Arg939Ser (c.2817A>T) is classified Conflicting classifications of pathogenicity in ACACB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0531); Rare (popmax 0.149%, afr); Associated with ACACB-related disorder.

What condition is associated with ACACB p.Arg939Ser (c.2817A>T)?

ACACB p.Arg939Ser (c.2817A>T) is associated with ACACB-related disorder (ClinVar).

How common is ACACB p.Arg939Ser (c.2817A>T) in the general population?

ACACB p.Arg939Ser (c.2817A>T) is rare (popmax 0.149%, afr) (gnomAD).

What do computational predictors say about ACACB p.Arg939Ser (c.2817A>T)?

AlphaMissense predicts likely benign (score 0.0531) — an in-silico prediction, not a clinical call.

ACACB p.Arg939Ser

c.2817A>T · rs144385811 · VCV2634738

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0531 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACACB-related disorder

Computational evidence

Protein change
AlphaMissense	0.0531	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -0.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -3.5
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	0.148	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 0.149% African / African-American · 112/75,050 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00979% 158/1,614,200 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.149%	670
Middle Eastern	0.0495%	2,021
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.000847%	118,004

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.Arg939Ser
Coding: c.2817A>T
MANE Select: NM_001093
dbSNP: rs144385811
Type: single nucleotide variant
Location: chr12:109201605 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 939: a β-strand; the biotinyl-binding domain

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

Disease context

ACACB-related disorder

Similar variants

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
ACACB c.1819-7A>G Likely benign same condition
ACACB c.1980+9T>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-arg939ser (accessed [today's date]).

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