Is CCN6 p.Cys247fs (c.740_741del) pathogenic?

CCN6 p.Cys247fs (c.740741del) is classified Pathogenic/Likely pathogenic in CCN6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-25). Very rare (popmax 0.0044%, sas); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Cys247fs (c.740_741del)?

CCN6 p.Cys247fs (c.740_741del) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Cys247fs (c.740_741del) in the general population?

CCN6 p.Cys247fs (c.740_741del) is very rare (popmax 0.0044%, sas) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

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

CCN6 p.Cys247fs

c.740_741del · rs727503755 · VCV166615

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (4 of 5, 46 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.017	GERP -3.1, phastCons 0.79
Overall
CADD	34.0	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 0.0044% South Asian · 4/90,968 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000558% 9/1,613,004 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,742
Remaining individualsnot grpmax-eligible	0.0016%	62,422
European (non-Finnish)	0.000339%	294,870

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.Cys247fs
Coding: c.740_741del
MANE Select: NM_198239
dbSNP: rs727503755
Type: Microsatellite
Location: chr6:112068352 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 247: 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.Leu14fs Pathogenic/Likely pathogenic ★★ same condition
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.Cys209fs 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

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-cys247fs (accessed [today's date]).

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