Is CCN1 p.Cys53Arg (c.157T>C) pathogenic?

CCN1 p.Cys53Arg (c.157T>C) is classified Uncertain significance in CCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely pathogenic (0.9844); Very rare (popmax 0.00102%, nfe).

How common is CCN1 p.Cys53Arg (c.157T>C) in the general population?

CCN1 p.Cys53Arg (c.157T>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CCN1 p.Cys53Arg (c.157T>C)?

AlphaMissense predicts likely pathogenic (score 0.9844) — an in-silico prediction, not a clinical call.

CCN1 p.Cys53Arg

c.157T>C · VCV3997530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9844	likely pathogenic
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -15.06	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 7.9	GERP 2.1, phastCons 1
Overall
CADD	32.0	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

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,504 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000822% 12/1,459,570 alleles · very rare

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: CCN1
Protein: p.Cys53Arg
Coding: c.157T>C
MANE Select: NM_001237 · reported on NM_001554
Type: single nucleotide variant
Location: chr1:85581458 (GRCh38)
Structure: AlphaFold pLDDT 73.80 · 115 PDB

Full CCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC9 p.Ala438Val Uncertain significance ★★ ⚠ same type
CCN1 c.277+50G>C Benign ★★ same type
CCN1 c.64-124G>A Benign ★★ same type
CCN1 c.-107C>A Benign ★★ same type
CCN1 p.Ser316Cys Likely benign ★★ ⚠ same type
CCN1 p.Tyr300= Benign ★★ same type
CCNA2 c.*828C>G Benign ★★ same type
CCNA2 p.Leu126= Benign ★★ 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/ccn1-p-cys53arg (accessed [today's date]).

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