Is CCN6 p.Tyr109= (c.327C>T) pathogenic?

CCN6 p.Tyr109= (c.327C>T) is classified Benign/Likely benign in CCN6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Rare (popmax 0.363%, afr); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Tyr109= (c.327C>T)?

CCN6 p.Tyr109= (c.327C>T) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Tyr109= (c.327C>T) in the general population?

CCN6 p.Tyr109= (c.327C>T) is rare (popmax 0.363%, afr) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

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

CCN6 p.Tyr109=

c.327C>T · rs145747429 · VCV355064

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.363%, afr)

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP -2.8
Overall
CADD	10.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.363% African / African-American · 272/75,032 alleles

Filtering AF 0.327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.313%

Overall 0.025% 404/1,614,156 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.363%	276
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Admixed American	0.0283%	3,531
South Asian	0.0143%	7,007
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
European (non-Finnish)	0.00576%	17,353
Finnishnot grpmax-eligible	0.00312%	32,007

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.Tyr109=
Coding: c.327C>T
MANE Select: NM_198239
dbSNP: rs145747429
Type: single nucleotide variant
Location: chr6:112061269 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 109: a disulfide bond; a UniProt-annotated variant site (in pprd); the igfbp n-terminal 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.Tyr109Ter Pathogenic ★ same residue
CCN6 p.Tyr109Ser 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

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-tyr109 (accessed [today's date]).

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