Is CD40 p.Cys83Arg (c.247T>C) pathogenic?

CD40 p.Cys83Arg (c.247T>C) is classified Pathogenic in CD40 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2010-12-23). AlphaMissense: likely pathogenic (0.9553); Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Cys83Arg (c.247T>C)?

CD40 p.Cys83Arg (c.247T>C) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Cys83Arg (c.247T>C) in the general population?

CD40 p.Cys83Arg (c.247T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD40 p.Cys83Arg (c.247T>C)?

AlphaMissense predicts likely pathogenic (score 0.9553) — an in-silico prediction, not a clinical call.

CD40 p.Cys83Arg

c.247T>C · rs28931586 · VCV17749

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9553 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.9553	likely pathogenic ✓ concordant with ClinVar · top 3% in CD40
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -13.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	26.5	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: CD40
Protein: p.Cys83Arg
Coding: c.247T>C
MANE Select: NM_001250
dbSNP: rs28931586
Type: single nucleotide variant
Location: chr20:46122349 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 83: a disulfide bond; a UniProt-annotated variant site (in higm3)

Full CD40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyper-IgM syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD40 p.Cys83= Conflicting classifications of pathogenicity ★ same residue
CD40 c.*178G>A Uncertain significance ★★ same condition
CD40 c.*547A>T Uncertain significance ★★ same condition
CD40 c.403+20A>G Benign/Likely benign ★★ same condition
CD40 c.52-15C>T Benign/Likely benign ★★ same condition
CD40 c.559+36G>C Benign ★★ same condition
CD40 c.-1T>C Benign/Likely benign ★★ same condition
CD40 c.*135C>G Benign ★★ same condition

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/cd40-p-cys83arg (accessed [today's date]).

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