Is ARPC1B p.Ala249Val (c.746C>T) pathogenic?

ARPC1B p.Ala249Val (c.746C>T) is classified Uncertain significance in ARPC1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-18). AlphaMissense: likely benign (0.297); Very rare (popmax 0.00667%, amr).

How common is ARPC1B p.Ala249Val (c.746C>T) in the general population?

ARPC1B p.Ala249Val (c.746C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ARPC1B p.Ala249Val (c.746C>T)?

AlphaMissense predicts likely benign (score 0.297) — an in-silico prediction, not a clinical call.

ARPC1B p.Ala249Val

c.746C>T · rs754153254 · VCV1357054

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.297 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.297	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -8.79	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 8,771 bp · p 0.0087 · regional, not allelic
Overall
CADD	24.8	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 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00242% 39/1,613,926 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00267%	37,452
European (non-Finnish)	0.00237%	42,143
South Asian	0.0022%	45,522

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: ARPC1B
Protein: p.Ala249Val
Coding: c.746C>T
MANE Select: NM_005720
dbSNP: rs754153254
Type: single nucleotide variant
Location: chr7:99391216 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.81 · 4 PDB
Residue 249: a β-strand

Full ARPC1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARPC1B p.Ala249= Likely benign ★★ same residue
ARPC1B c.392+2T>C Pathogenic ★★ same type
ARPC1B c.64+2T>A Pathogenic ★★ same type
ARPC1B p.Ala261= Pathogenic ★★ same type
ARPC1B c.1080+4A>C Uncertain significance ★★ same type
ARPC1B c.170-3C>T Uncertain significance ★★ same type
ARPC1B c.501-5G>A Uncertain significance ★★ same type
ARPC1B p.Ala238Val Uncertain significance ★★ ⚠ 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/arpc1b-p-ala249val (accessed [today's date]).

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