Is CCN6 p.Lys208fs (c.624del) pathogenic?

CCN6 p.Lys208fs (c.624del) is classified Pathogenic in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-25). Ultra-rare (popmax 0.0138%, amr).

How common is CCN6 p.Lys208fs (c.624del) in the general population?

CCN6 p.Lys208fs (c.624del) is ultra-rare (popmax 0.0138%, amr) (gnomAD).

CCN6 p.Lys208fs

c.624del · rs781790231 · VCV2734930

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, amr)

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 4 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Overall
CADD	33.0	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 0.0138% Admixed American · 8/58,164 alleles

Filtering AF 0.00679% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00495%

Overall 0.00357% 57/1,597,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0138%	7,271
Ashkenazi Jewishnot grpmax-eligible	0.00685%	14,591
Remaining individualsnot grpmax-eligible	0.00647%	15,446
African / African-American	0.00542%	18,442
East Asian	0.0045%	22,214
South Asian	0.00338%	29,597
European (non-Finnish)	0.0029%	34,455

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.Lys208fs
Coding: c.624del
MANE Select: NM_198239
dbSNP: rs781790231
Type: Deletion
Location: chr6:112068231 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 208: a UniProt-annotated variant site (in pprd); the tsp type-1 domain

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

Similar variants

CCN6 p.Lys208Ter Pathogenic ★ same residue
CCN6 p.Lys208Asn Uncertain significance ★ ⚠ same residue
CCN6 p.Lys208Thr Uncertain significance ★ ⚠ same residue
CCN6 p.Asn178_Cys179insTer Pathogenic ★★ same type
CCN6 p.Glu84fs Pathogenic ★★ same type
CCN6 p.Ser236fs Pathogenic ★★ same type
CCN6 c.783+1_783+6del Pathogenic ★ same type
CCN6 p.Ala15fs 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-lys208fs (accessed [today's date]).

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