Is CD40 p.Cys83= (c.249C>T) pathogenic?

CD40 p.Cys83= (c.249C>T) is classified Conflicting classifications of pathogenicity in CD40 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-03). Very rare (popmax 0.00934%, afr); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Cys83= (c.249C>T)?

CD40 p.Cys83= (c.249C>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Cys83= (c.249C>T) in the general population?

CD40 p.Cys83= (c.249C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

CD40 p.Cys83=

c.249C>T · rs776893342 · VCV896159

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -11	GERP -3
Overall
CADD	6.425	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,922 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00353% 57/1,614,072 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,703
Admixed American	0.00833%	12,001
European (non-Finnish)	0.00364%	27,443
Finnishnot grpmax-eligible	0.00156%	64,036
South Asian	0.0011%	91,074

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: CD40
Protein: p.Cys83=
Coding: c.249C>T
MANE Select: NM_001250
dbSNP: rs776893342
Type: single nucleotide variant
Location: chr20:46122351 (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.Cys83Arg Pathogenic 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-cys83 (accessed [today's date]).

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