Is CCN6 p.Leu10Pro (c.29T>C) pathogenic?

CCN6 p.Leu10Pro (c.29T>C) is classified Uncertain significance in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-14). AlphaMissense: likely benign (0.1518); Very rare (popmax 8.47e-05%, nfe); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Leu10Pro (c.29T>C)?

CCN6 p.Leu10Pro (c.29T>C) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Leu10Pro (c.29T>C) in the general population?

CCN6 p.Leu10Pro (c.29T>C) is very rare (popmax 8.47e-05%, nfe) (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.Leu10Pro (c.29T>C)?

AlphaMissense predicts likely benign (score 0.1518) — an in-silico prediction, not a clinical call.

CCN6 p.Leu10Pro

c.29T>C · rs1776282450 · VCV1030720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
AlphaMissense	0.1518	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -11.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	23.3	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 8.47e-05% European (non-Finnish) · 1/1,179,976 alleles

Overall 6.84e-05% 1/1,461,864 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.Leu10Pro
Coding: c.29T>C
MANE Select: NM_198239
dbSNP: rs1776282450
Type: single nucleotide variant
Location: chr6:112054386 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30

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.Leu10= 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
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-leu10pro (accessed [today's date]).

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