Is CD96 p.Ile240fs (c.718dup) pathogenic?

CD96 p.Ile240fs (c.718dup) is classified Uncertain significance in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-02). Very rare (popmax 0.00229%, nfe); Associated with C syndrome.

What condition is associated with CD96 p.Ile240fs (c.718dup)?

CD96 p.Ile240fs (c.718dup) is associated with C syndrome (ClinVar).

How common is CD96 p.Ile240fs (c.718dup) in the general population?

CD96 p.Ile240fs (c.718dup) is very rare (popmax 0.00229%, nfe) (gnomAD).

CD96 p.Ile240fs

c.718dup · rs766366613 · VCV816889

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Conditions

C syndrome

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 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9	GERP -1.6
Overall
CADD	21.8	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 0.00229% European (non-Finnish) · 27/1,176,938 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00168% 27/1,610,720 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: CD96
Protein: p.Ile240fs
Coding: c.718dup
MANE Select: NM_005816
dbSNP: rs766366613
Type: Duplication
Location: chr3:111579197 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 240: a disulfide bond

Full CD96 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

C syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD96 p.Val19fs Conflicting classifications of pathogenicity ★ same condition
CD96 c.1249+1G>A Uncertain significance ★★ same condition
CD96 p.Asp312fs Uncertain significance ★★ same condition
CD96 c.807+14A>C Benign/Likely benign ★★ same condition
CD96 c.1321+1G>A Likely pathogenic ★ same condition
CD96 c.807+2T>A Likely pathogenic ★ same condition
CD96 c.1181-12T>C Uncertain significance ★ same condition
CD96 c.544-1477_544-1459del Uncertain significance ★ 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/cd96-p-ile240fs (accessed [today's date]).

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