Is ACACB p.Val531Ile (c.1591G>A) pathogenic?

ACACB p.Val531Ile (c.1591G>A) is classified Likely benign in ACACB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0464); Very rare (popmax 0.00833%, amr).

How common is ACACB p.Val531Ile (c.1591G>A) in the general population?

ACACB p.Val531Ile (c.1591G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ACACB p.Val531Ile (c.1591G>A)?

AlphaMissense predicts likely benign (score 0.0464) — an in-silico prediction, not a clinical call.

ACACB p.Val531Ile

c.1591G>A · VCV4201025

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0464	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -2.99	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 4.6	GERP -0.083, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 111 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	12.81	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000744% 12/1,613,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
African / African-American	0.00133%	74,932
South Asian	0.0011%	91,066
European (non-Finnish)	0.000424%	236,006

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.Val531Ile
Coding: c.1591G>A
MANE Select: NM_001093
Type: single nucleotide variant
Location: chr12:109179241 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29 · 11 PDB
Residue 531: the biotin carboxylation domain; the atp-grasp domain; a β-strand

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

Similar variants

ACACB p.Val531= Benign ★★ 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-val531ile (accessed [today's date]).

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