Is CD28 p.Leu169Ile (c.505C>A) pathogenic?

CD28 p.Leu169Ile (c.505C>A) is classified Uncertain significance in CD28 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely benign (0.0944); Absent from gnomAD v4.1.

How common is CD28 p.Leu169Ile (c.505C>A) in the general population?

CD28 p.Leu169Ile (c.505C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD28 p.Leu169Ile (c.505C>A)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

CD28 p.Leu169Ile

c.505C>A · rs199840923 · VCV2556924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.8	GERP -4.6
Regional constraint	o/e 0.99	unconstrained · MANE · 5,256 bp · p 0.94 · regional, not allelic
Overall
CADD	13.06	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

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.Leu169Ile
Coding: c.505C>A
MANE Select: NM_006139
dbSNP: rs199840923
Type: single nucleotide variant
Location: chr2:203729743 (GRCh38)
Gene constraint: LOEUF 0.634 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 169: 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-leu169ile (accessed [today's date]).

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