Is CCN6 p.Met1Val (c.1A>G) pathogenic?

CCN6 p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in CCN6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.033%, mid); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Met1Val (c.1A>G)?

CCN6 p.Met1Val (c.1A>G) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Met1Val (c.1A>G) in the general population?

CCN6 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

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

CCN6 p.Met1Val

c.1A>G · rs1776281365 · VCV1680451

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.536	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	19.69	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000958% 14/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.0107%	9,368
Remaining individualsnot grpmax-eligible	0.0064%	15,625

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.Met1Val
Coding: c.1A>G
MANE Select: NM_198239
dbSNP: rs1776281365
Type: single nucleotide variant
Location: chr6:112054358 (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.Met1Ile Pathogenic ★ same residue
CCN6 p.Met1Lys Pathogenic ★ same residue
CCN6 p.Met1Thr Pathogenic ★ 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

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-met1val (accessed [today's date]).

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