Is CD28 p.Gly18Arg (c.52G>A) pathogenic?

CD28 p.Gly18Arg (c.52G>A) is classified Pathogenic in CD28 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.2289); Absent from gnomAD v4.1; Associated with immunodeficiency 123 with HPV-related verrucosis.

What condition is associated with CD28 p.Gly18Arg (c.52G>A)?

CD28 p.Gly18Arg (c.52G>A) is associated with immunodeficiency 123 with HPV-related verrucosis (ClinVar).

How common is CD28 p.Gly18Arg (c.52G>A) in the general population?

CD28 p.Gly18Arg (c.52G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD28 p.Gly18Arg (c.52G>A)?

AlphaMissense predicts likely benign (score 0.2289) — an in-silico prediction, not a clinical call.

CD28 p.Gly18Arg

c.52G>A · VCV3256912

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2289 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency 123 with HPV-related verrucosis

Computational evidence

Protein change
AlphaMissense	0.2289	likely benign ⚠ discordant with ClinVar
REVEL	0.434	indeterminate
SaProt	LLR -10.45	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.34	loss · gain 0.00 · SpliceAI calls gain · independent
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	29.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CD28
Protein: p.Gly18Arg
Coding: c.52G>A
MANE Select: NM_006139
Type: single nucleotide variant
Location: chr2:203706748 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 18: a UniProt-annotated variant site (in imd123; likely pathogenic; the underlying nucleotide substitution affects splicing; patient-derived cells contain normally spliced transcripts with the missense variant and aberrant splice transcripts that probably undergo nonsense-mediated decay; significantly decreased cd28 mrna levels in homozygous patient-derived t cells compared to controls; decreased function in t cell activation)

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

Disease context

immunodeficiency 123 with HPV-related verrucosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Gly83Arg Uncertain significance ★ ⚠ same type
CD28 p.Gly88Ala 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-gly18arg (accessed [today's date]).

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