Is ARPC4 p.Val76Ala (c.227T>C) pathogenic?

ARPC4 p.Val76Ala (c.227T>C) is classified Uncertain significance in ARPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-06). AlphaMissense: likely pathogenic (0.9819); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ARPC4 p.Val76Ala (c.227T>C)?

ARPC4 p.Val76Ala (c.227T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ARPC4 p.Val76Ala (c.227T>C) in the general population?

ARPC4 p.Val76Ala (c.227T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARPC4 p.Val76Ala (c.227T>C)?

AlphaMissense predicts likely pathogenic (score 0.9819) — an in-silico prediction, not a clinical call.

ARPC4 p.Val76Ala

c.227T>C · VCV4863644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9819 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9819	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -11.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 13 kb · p 7.2e-15 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARPC4
Protein: p.Val76Ala
Coding: c.227T>C
MANE Select: NM_005718
Type: single nucleotide variant
Location: chr3:9800289 (GRCh38)
Gene constraint: LOEUF 0.362 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.20 · 5 PDB

Full ARPC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARPC4 c.3+11C>G Uncertain significance ★ same condition
ARPC4 c.3+11C>T Uncertain significance ★ same condition
ARPC4 c.3+16C>T Uncertain significance ★ same condition
ARPC4 c.3+17C>A Uncertain significance ★ same condition
ARPC4 c.3+20G>A Uncertain significance ★ same condition
ARPC4 c.3+38G>A Uncertain significance ★ same condition
ARPC4 c.3+47C>T Uncertain significance ★ same condition
ARPC4 c.3+55T>G Uncertain significance ★ 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/arpc4-p-val76ala (accessed [today's date]).

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