Is CD28 p.Ile176Phe (c.526A>T) pathogenic?

CD28 p.Ile176Phe (c.526A>T) is classified Uncertain significance in CD28 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-09). AlphaMissense: likely benign (0.0644); Very rare (popmax 0.00229%, nfe).

How common is CD28 p.Ile176Phe (c.526A>T) in the general population?

CD28 p.Ile176Phe (c.526A>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about CD28 p.Ile176Phe (c.526A>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

CD28 p.Ile176Phe

c.526A>T · VCV3829488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -6.59	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 -0.016	GERP -4.6
Regional constraint	o/e 0.99	unconstrained · MANE · 5,256 bp · p 0.94 · regional, not allelic
Overall
CADD	0.007	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 0.00229% European (non-Finnish) · 27/1,179,736 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,613,202 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,694
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00134%	74,798

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.Ile176Phe
Coding: c.526A>T
MANE Select: NM_006139
Type: single nucleotide variant
Location: chr2:203729764 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 176: an α-helix

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.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-ile176phe (accessed [today's date]).

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