Is CD28 p.Gly83Arg (c.247G>C) pathogenic?

CD28 p.Gly83Arg (c.247G>C) is classified Uncertain significance in CD28 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3485); Ultra-rare (popmax 0.0813%, sas).

How common is CD28 p.Gly83Arg (c.247G>C) in the general population?

CD28 p.Gly83Arg (c.247G>C) is ultra-rare (popmax 0.0813%, sas) (gnomAD).

What do computational predictors say about CD28 p.Gly83Arg (c.247G>C)?

AlphaMissense predicts ambiguous (score 0.3485) — an in-silico prediction, not a clinical call.

CD28 p.Gly83Arg

c.247G>C · VCV4650560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3485 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3485	ambiguous
REVEL	0.131	moderately benign-leaning
SaProt	LLR -9.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.67 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0813% South Asian · 74/91,074 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0608%

Overall 0.00471% 76/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0813%	1,231
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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: CD28
Protein: p.Gly83Arg
Coding: c.247G>C
MANE Select: NM_006139
Type: single nucleotide variant
Location: chr2:203726827 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 83: a disulfide bond; a β-strand; the ig-like v-type domain

Full CD28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD28 p.Ala35= Benign ★★ same type
CD28 p.Arg203Cys Uncertain significance ★ ⚠ same type
CD28 p.Asn19Asp Uncertain significance ★ ⚠ same type
CD28 p.Asn45Ser Uncertain significance ★ ⚠ same type
CD28 p.Gln15Arg Uncertain significance ★ ⚠ same type
CD28 p.Glu93Lys Uncertain significance ★ ⚠ same type
CD28 p.Gly88Ala Uncertain significance ★ ⚠ same type
CD28 p.Ile176Phe 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/cd28-p-gly83arg (accessed [today's date]).

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