Is CCN4 p.Arg294Cys (c.880C>T) pathogenic?

CCN4 p.Arg294Cys (c.880C>T) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.2375); Ultra-rare (popmax 0.07%, amr).

How common is CCN4 p.Arg294Cys (c.880C>T) in the general population?

CCN4 p.Arg294Cys (c.880C>T) is ultra-rare (popmax 0.07%, amr) (gnomAD).

What do computational predictors say about CCN4 p.Arg294Cys (c.880C>T)?

AlphaMissense predicts likely benign (score 0.2375) — an in-silico prediction, not a clinical call.

CCN4 p.Arg294Cys

c.880C>T · VCV4649985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.07%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2375	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -12.17	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.58, phastCons 0.36
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	25.7	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 0.07% Admixed American · 42/60,004 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0473%

Overall 0.00496% 80/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.07%	1,429
East Asian	0.00891%	11,223
European (non-Finnish)	0.00263%	38,066
South Asian	0.0022%	45,543
African / African-American	0.00133%	74,936

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: CCN4
Protein: p.Arg294Cys
Coding: c.880C>T
MANE Select: NM_003882
Type: single nucleotide variant
Location: chr8:133227486 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 294: a disulfide bond; the ctck domain

Full CCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN4 p.Arg97= Benign ★★ same type
CCN4 p.Leu99= Benign ★★ same type
CCN4 p.Thr145Met Likely benign ★★ ⚠ same type
CCN4 p.Ala10Glu Uncertain significance ★ ⚠ same type
CCN4 p.Ala10Thr Uncertain significance ★ ⚠ same type
CCN4 p.Ala17Ser Uncertain significance ★ ⚠ same type
CCN4 p.Ala196Thr Uncertain significance ★ ⚠ same type
CCN4 p.Ala243Ser 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/ccn4-p-arg294cys (accessed [today's date]).

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