Is CD96 p.Cys515Arg (c.1543T>C) pathogenic?

CD96 p.Cys515Arg (c.1543T>C) is classified Uncertain significance in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-07). AlphaMissense: likely pathogenic (0.7183); Very rare (popmax 0.000849%, nfe); Associated with C syndrome.

What condition is associated with CD96 p.Cys515Arg (c.1543T>C)?

CD96 p.Cys515Arg (c.1543T>C) is associated with C syndrome (ClinVar).

How common is CD96 p.Cys515Arg (c.1543T>C) in the general population?

CD96 p.Cys515Arg (c.1543T>C) is very rare (popmax 0.000849%, nfe) (gnomAD).

What do computational predictors say about CD96 p.Cys515Arg (c.1543T>C)?

AlphaMissense predicts likely pathogenic (score 0.7183) — an in-silico prediction, not a clinical call.

CD96 p.Cys515Arg

c.1543T>C · VCV3779020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

C syndrome

Computational evidence

Protein change
AlphaMissense	0.7183	likely pathogenic · top 6% in CD96
REVEL	0.136	moderately benign-leaning
SaProt	LLR -11.41	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.092	GERP -2.3
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	16.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C531R vs ClinVar C515R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000849% European (non-Finnish) · 10/1,177,500 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000685% 10/1,458,976 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.Cys515Arg
Coding: c.1543T>C
MANE Select: NM_005816
Type: single nucleotide variant
Location: chr3:111647608 (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 c.1249+1G>A 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 p.Asn464Asp Uncertain significance ★ ⚠ same condition
CD96 p.Asp265Gly Uncertain significance ★ ⚠ same condition
CD96 p.Leu342Gln 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-cys515arg (accessed [today's date]).

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