Is CCN6 p.Ala197Pro (c.589G>C) pathogenic?

CCN6 p.Ala197Pro (c.589G>C) is classified Pathogenic/Likely pathogenic in CCN6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1567); Very rare (popmax 0.000593%, nfe); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Ala197Pro (c.589G>C)?

CCN6 p.Ala197Pro (c.589G>C) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Ala197Pro (c.589G>C) in the general population?

CCN6 p.Ala197Pro (c.589G>C) is very rare (popmax 0.000593%, 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.Ala197Pro (c.589G>C)?

AlphaMissense predicts likely benign (score 0.1567) — an in-silico prediction, not a clinical call.

CCN6 p.Ala197Pro

c.589G>C · rs1554313639 · VCV637051

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
AlphaMissense	0.1567	likely benign ⚠ discordant with ClinVar
REVEL	0.607	indeterminate
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.43	donor loss · deltas
Pangolin	Δ0.22	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	33.0	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 0.000593% European (non-Finnish) · 7/1,179,910 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,844 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.Ala197Pro
Coding: c.589G>C
MANE Select: NM_198239
dbSNP: rs1554313639
Type: single nucleotide variant
Location: chr6:112064997 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 197: a UniProt-annotated variant site (in pprd)

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 c.49-1G>A Pathogenic/Likely pathogenic ★★ same condition
CCN6 c.590-1G>C 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
CCN6 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
CCN6 p.Ser39Ter 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-ala197pro (accessed [today's date]).

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