Is CCN6 p.Ser290fs (c.866dup) pathogenic?

CCN6 p.Ser290fs (c.866dup) is classified Pathogenic in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). Very rare (popmax 0.00446%, eas).

How common is CCN6 p.Ser290fs (c.866dup) in the general population?

CCN6 p.Ser290fs (c.866dup) is very rare (popmax 0.00446%, eas) (gnomAD).

CCN6 p.Ser290fs

c.866dup · rs782450077 · VCV2734934

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -0.41, phastCons 0.64
Overall
CADD	29.8	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 0.00446% East Asian · 2/44,834 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000434% 7/1,613,594 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,417
South Asian	0.0011%	91,078
European (non-Finnish)	0.000339%	294,974

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.Ser290fs
Coding: c.866dup
MANE Select: NM_198239
dbSNP: rs782450077
Type: Duplication
Location: chr6:112069420 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 290: a disulfide bond; a UniProt-annotated variant site (in pprd); the ctck domain

Full CCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN6 p.Cys209fs Pathogenic ★★ same type
CCN6 p.Gln289fs Pathogenic/Likely pathogenic ★★ same type
CCN6 c.48+2dup Pathogenic ★ same type
CCN6 p.Glu243fs Pathogenic ★ same type
CCN6 p.Leu160fs Pathogenic ★ same type
CCN6 p.Ser228fs Pathogenic ★ same type
CCN6 p.Thr267fs Pathogenic ★ same type
CCN6 p.Thr294fs Pathogenic ★ same type

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-ser290fs (accessed [today's date]).

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