Is CCN6 p.Cys100Ser (c.298T>A) pathogenic?

CCN6 p.Cys100Ser (c.298T>A) is classified Likely pathogenic in CCN6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 0.0011%, sas); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Cys100Ser (c.298T>A)?

CCN6 p.Cys100Ser (c.298T>A) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Cys100Ser (c.298T>A) in the general population?

CCN6 p.Cys100Ser (c.298T>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CCN6 p.Cys100Ser (c.298T>A)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

CCN6 p.Cys100Ser

c.298T>A · VCV3385337

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic ✓ concordant with ClinVar · top 1% in CCN6
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -12.70	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 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	27.4	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

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 6.84e-05% 1/1,461,882 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: CCN6
Protein: p.Cys100Ser
Coding: c.298T>A
MANE Select: NM_198239
Type: single nucleotide variant
Location: chr6:112061240 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 100: a disulfide bond; a UniProt-annotated variant site (in pprd); the igfbp n-terminal domain; a UniProt-annotated variant site (in pprd; uncertain significance)

Full CCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive pseudorheumatoid arthropathy of childhood — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive pseudorheumatoid dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CCN6 p.Cys100Arg Uncertain significance ★ ⚠ same residue
CCN6 c.49-1G>A Pathogenic/Likely pathogenic ★★ same condition
CCN6 c.590-1G>C Likely pathogenic ★★ same condition
CCN6 p.Ala197Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCN6 p.Cys223Gly Pathogenic ★★ same condition
CCN6 p.Cys337Tyr Pathogenic/Likely pathogenic ★★ same condition
CCN6 p.Cys52Ter Pathogenic/Likely pathogenic ★★ same condition
CCN6 p.Cys78Tyr Pathogenic/Likely pathogenic ★★ 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/ccn6-p-cys100ser (accessed [today's date]).

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