Is CCN4 p.Arg172Ser (c.514C>A) pathogenic?

CCN4 p.Arg172Ser (c.514C>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.3046); Absent from gnomAD v4.1.

How common is CCN4 p.Arg172Ser (c.514C>A) in the general population?

CCN4 p.Arg172Ser (c.514C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCN4 p.Arg172Ser (c.514C>A)?

AlphaMissense predicts likely benign (score 0.3046) — an in-silico prediction, not a clinical call.

CCN4 p.Arg172Ser

c.514C>A · VCV3997556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3046	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -11.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.059	GERP -2, phastCons 0.003
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	16.4	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: CCN4
Protein: p.Arg172Ser
Coding: c.514C>A
MANE Select: NM_003882
Type: single nucleotide variant
Location: chr8:133220745 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 172: the vwfc domain

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

Similar variants

CCN4 p.Arg172His Uncertain significance ★ ⚠ same residue
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

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-arg172ser (accessed [today's date]).

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