Is CCN6 p.Ala15fs (c.43_44del) pathogenic?

CCN6 p.Ala15fs (c.4344del) is classified Pathogenic in CCN6 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-07). Very rare (popmax 0.00334%, amr); Associated with progressive pseudorheumatoid arthropathy of childhood.

What condition is associated with CCN6 p.Ala15fs (c.43_44del)?

CCN6 p.Ala15fs (c.43_44del) is associated with progressive pseudorheumatoid arthropathy of childhood (ClinVar).

How common is CCN6 p.Ala15fs (c.43_44del) in the general population?

CCN6 p.Ala15fs (c.43_44del) is very rare (popmax 0.00334%, amr) (gnomAD).

How is Progressive pseudorheumatoid dysplasia inherited?

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

CCN6 p.Ala15fs

c.43_44del · rs1554311394 · VCV6386

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

progressive pseudorheumatoid arthropathy of childhood

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3	GERP -0.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,932 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000479% 7/1,461,810 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,966
European (non-Finnish)	0.000424%	235,978

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.Ala15fs
Coding: c.43_44del
MANE Select: NM_198239
dbSNP: rs1554311394
Type: Deletion
Location: chr6:112054400 (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.Glu84fs Pathogenic ★★ same condition
CCN6 p.Ser236fs Pathogenic ★★ same condition
CCN6 p.Ala15Thr Uncertain significance ★★ ⚠ same residue
CCN6 p.Leu246fs Pathogenic ★ same condition
CCN6 p.Pro26fs Likely pathogenic ★ same condition
CCN6 p.Tyr198_Asn200delinsTer Pathogenic ★ same condition
CCN6 p.Phe280fs Pathogenic same condition
CCN6 p.Val231fs 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-ala15fs (accessed [today's date]).

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