Is CD28 p.Glu93Lys (c.277G>A) pathogenic?

CD28 p.Glu93Lys (c.277G>A) is classified Uncertain significance in CD28 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.15); Ultra-rare (popmax 0.0133%, amr).

How common is CD28 p.Glu93Lys (c.277G>A) in the general population?

CD28 p.Glu93Lys (c.277G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CD28 p.Glu93Lys (c.277G>A)?

AlphaMissense predicts likely benign (score 0.15) — an in-silico prediction, not a clinical call.

CD28 p.Glu93Lys

c.277G>A · rs747837891 · VCV3140491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.15 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.15	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.67 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,002 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00204% 33/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00186%	53,635

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.Glu93Lys
Coding: c.277G>A
MANE Select: NM_006139
dbSNP: rs747837891
Type: single nucleotide variant
Location: chr2:203726857 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 93: 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.Gly83Arg 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-glu93lys (accessed [today's date]).

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