Is CCN6 p.Ser236fs (c.707del) pathogenic?

CCN6 p.Ser236fs (c.707del) is classified Pathogenic in CCN6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-04). Very rare (popmax 0.00167%, amr); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Ser236fs (c.707del)?

CCN6 p.Ser236fs (c.707del) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Ser236fs (c.707del) in the general population?

CCN6 p.Ser236fs (c.707del) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

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

CCN6 p.Ser236fs

c.707del · rs1583586843 · VCV817946

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.5	GERP -5.4, phastCons 1
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,946 alleles

Overall 0.000657% 1/152,160 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.Ser236fs
Coding: c.707del
MANE Select: NM_198239
dbSNP: rs1583586843
Type: Deletion
Location: chr6:112068322 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 236: a UniProt-annotated variant site (in pprd); the tsp type-1 domain

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.Glu84fs Pathogenic ★★ same condition
CCN6 p.Ala15fs Pathogenic ★ same condition
CCN6 p.Leu246fs Pathogenic ★ same condition
CCN6 p.Pro26fs Likely pathogenic ★ same condition
CCN6 p.Tyr198_Asn200delinsTer Pathogenic ★ same condition
CCN6 p.Phe280fs Pathogenic same condition
CCN6 p.Val231fs Pathogenic same condition
CCN6 c.49-1G>A 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-ser236fs (accessed [today's date]).

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