Is CD96 p.Ser421Cys (c.1261A>T) pathogenic?

CD96 p.Ser421Cys (c.1261A>T) is classified Uncertain significance in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1443); Very rare (popmax 0.00425%, nfe).

How common is CD96 p.Ser421Cys (c.1261A>T) in the general population?

CD96 p.Ser421Cys (c.1261A>T) is very rare (popmax 0.00425%, nfe) (gnomAD).

What do computational predictors say about CD96 p.Ser421Cys (c.1261A>T)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

CD96 p.Ser421Cys

c.1261A>T · VCV3998392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00425%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -10.86	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -2.6
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	16.49	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 S437C vs ClinVar S421C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00425% European (non-Finnish) · 50/1,175,744 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00329% 53/1,609,332 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00425%	23,515
Remaining individualsnot grpmax-eligible	0.00321%	31,161
African / African-American	0.00134%	74,858

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.Ser421Cys
Coding: c.1261A>T
MANE Select: NM_005816
Type: single nucleotide variant
Location: chr3:111624344 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 421: the 'disordered' region

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

Similar variants

CD96 p.Ser421Arg Uncertain significance ★ ⚠ same residue
CD96 c.1249+1G>A Uncertain significance ★★ same type
CD96 c.544-1512C>T Uncertain significance ★★ ⚠ same type
CD96 p.Asp205Gly Uncertain significance ★★ ⚠ same type
CD96 p.Asp224Asn Uncertain significance ★★ ⚠ same type
CD96 p.Ile151Thr Uncertain significance ★★ ⚠ same type
CD96 p.Leu120Pro Uncertain significance ★★ ⚠ same type
CD96 p.Lys500Arg Uncertain significance ★★ ⚠ 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/cd96-p-ser421cys (accessed [today's date]).

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