Is ARPC4 p.Arg158Cys (c.472C>T) pathogenic?

ARPC4 p.Arg158Cys (c.472C>T) is classified Conflicting classifications of pathogenicity in ARPC4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with developmental delay, language impairment, and ocular abnormalities.

What condition is associated with ARPC4 p.Arg158Cys (c.472C>T)?

ARPC4 p.Arg158Cys (c.472C>T) is associated with developmental delay, language impairment, and ocular abnormalities (ClinVar).

How common is ARPC4 p.Arg158Cys (c.472C>T) in the general population?

ARPC4 p.Arg158Cys (c.472C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARPC4 p.Arg158Cys (c.472C>T)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

ARPC4 p.Arg158Cys

c.472C>T · rs2125650298 · VCV1339815

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental delay, language impairment, and ocular abnormalities

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 2% in ARPC4
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 13 kb · p 7.2e-15 · regional, not allelic
Overall
CADD	29.4	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

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.Arg158Cys
Coding: c.472C>T
MANE Select: NM_005718
dbSNP: rs2125650298
Type: single nucleotide variant
Location: chr3:9803984 (GRCh38)
Gene constraint: LOEUF 0.362 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.20 · 5 PDB
Residue 158: an α-helix; a UniProt-annotated variant site (in devlo)

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

Disease context

developmental delay, language impairment, and ocular abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARPC4 p.Arg158His Pathogenic ★ same residue
ARPC4 p.Arg158= Likely benign ★ same residue
ARPC4 p.Arg156His Uncertain significance ★ ⚠ same condition
ARPC4 c.3+11C>G Uncertain significance ★ same type
ARPC4 c.3+11C>T Uncertain significance ★ same type
ARPC4 c.3+14G>C Uncertain significance ★ same type
ARPC4 c.3+16C>T Uncertain significance ★ same type
ARPC4 c.3+17C>A 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/arpc4-p-arg158cys (accessed [today's date]).

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