Is CD96 p.Arg227Gln (c.680G>A) pathogenic?

CD96 p.Arg227Gln (c.680G>A) is classified Likely benign in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). AlphaMissense: likely benign (0.0785); Rare (popmax 0.479%, eas).

How common is CD96 p.Arg227Gln (c.680G>A) in the general population?

CD96 p.Arg227Gln (c.680G>A) is rare (popmax 0.479%, eas) (gnomAD).

What do computational predictors say about CD96 p.Arg227Gln (c.680G>A)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

CD96 p.Arg227Gln

c.680G>A · rs143049331 · VCV342527

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.479%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.2
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	3.085	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 R243Q vs ClinVar R227Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.479% East Asian · 215/44,854 alleles

Filtering AF 0.427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.407%

Overall 0.0207% 333/1,609,396 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.479%	209
Remaining individualsnot grpmax-eligible	0.077%	1,299
African / African-American	0.0107%	9,370
South Asian	0.00549%	18,198
Admixed American	0.005%	20,006
European (non-Finnish)	0.00459%	21,771

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.Arg227Gln
Coding: c.680G>A
MANE Select: NM_005816
dbSNP: rs143049331
Type: single nucleotide variant
Location: chr3:111579163 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 227: a disulfide bond; the ig-like v-type 2 domain

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

Similar variants

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
CD96 p.Pro346Ser 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-arg227gln (accessed [today's date]).

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