Is CD96 p.Val19fs (c.54dup) pathogenic?

CD96 p.Val19fs (c.54dup) is classified Conflicting classifications of pathogenicity in CD96 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-30). Rare (popmax 0.537%, eas); Associated with C syndrome.

What condition is associated with CD96 p.Val19fs (c.54dup)?

CD96 p.Val19fs (c.54dup) is associated with C syndrome (ClinVar).

How common is CD96 p.Val19fs (c.54dup) in the general population?

CD96 p.Val19fs (c.54dup) is rare (popmax 0.537%, eas) (gnomAD).

CD96 p.Val19fs

c.54dup · rs200703204 · VCV225311

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.537%, eas)

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 1 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.8	GERP 2.3, phastCons 0.93
Overall
CADD	26.1	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 0.537% East Asian · 241/44,868 alleles

Filtering AF 0.481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.46%

Overall 0.0235% 379/1,613,716 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.537%	186
Admixed American	0.115%	870
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
Remaining individualsnot grpmax-eligible	0.0192%	5,208
South Asian	0.0121%	8,278
African / African-American	0.00267%	37,504
European (non-Finnish)	0.00229%	43,692

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.Val19fs
Coding: c.54dup
MANE Select: NM_005816
dbSNP: rs200703204
Type: Duplication
Location: chr3:111542298 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB

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.Ile240fs Uncertain significance ★ same condition
CD96 p.Val19= Likely benign ★ same residue
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

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-val19fs (accessed [today's date]).

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