Is CD40 p.Thr136= (c.408A>T) pathogenic?

CD40 p.Thr136= (c.408A>T) is classified Pathogenic in CD40 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-10-23). Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Thr136= (c.408A>T)?

CD40 p.Thr136= (c.408A>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Thr136= (c.408A>T) in the general population?

CD40 p.Thr136= (c.408A>T) is absent from gnomAD v4.1 (gnomAD).

CD40 p.Thr136=

c.408A>T · rs2145595063 · VCV17748

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.34	acceptor loss · deltas
Pangolin	Δ0.27	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.1	GERP 0.005, phastCons 0.069
Overall
CADD	4.328	PHRED · no single calibrated threshold — expert panels disagree

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.Thr136=
Coding: c.408A>T
MANE Select: NM_001250
dbSNP: rs2145595063
Type: single nucleotide variant
Location: chr20:46123130 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB

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.Thr136Ala Uncertain significance ★ ⚠ 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-thr136 (accessed [today's date]).

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