Is CCN6 p.Leu246Pro (c.737T>C) pathogenic?

CCN6 p.Leu246Pro (c.737T>C) is classified Likely pathogenic in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-21). AlphaMissense: likely pathogenic (0.9038); Absent from gnomAD v4.1; Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Leu246Pro (c.737T>C)?

CCN6 p.Leu246Pro (c.737T>C) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Leu246Pro (c.737T>C) in the general population?

CCN6 p.Leu246Pro (c.737T>C) is absent from gnomAD v4.1 (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.Leu246Pro (c.737T>C)?

AlphaMissense predicts likely pathogenic (score 0.9038) — an in-silico prediction, not a clinical call.

CCN6 p.Leu246Pro

c.737T>C · rs2546929180 · VCV3233835

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9038 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
AlphaMissense	0.9038	likely pathogenic ✓ concordant with ClinVar · top 9% in CCN6
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -14.33	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	27.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCN6
Protein: p.Leu246Pro
Coding: c.737T>C
MANE Select: NM_198239
dbSNP: rs2546929180
Type: single nucleotide variant
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 246: 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.Leu246fs Pathogenic ★ same residue
CCN6 p.Leu246= Likely benign ★ 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-leu246pro (accessed [today's date]).

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