Is CD40 p.Thr57Met (c.170C>T) pathogenic?

CD40 p.Thr57Met (c.170C>T) is classified Conflicting classifications of pathogenicity in CD40 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.3552); Very rare (popmax 8.47e-05%, nfe); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Thr57Met (c.170C>T)?

CD40 p.Thr57Met (c.170C>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Thr57Met (c.170C>T) in the general population?

CD40 p.Thr57Met (c.170C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CD40 p.Thr57Met (c.170C>T)?

AlphaMissense predicts ambiguous (score 0.3552) — an in-silico prediction, not a clinical call.

CD40 p.Thr57Met

c.170C>T · rs2515708347 · VCV2138350

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3552 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.3552	ambiguous
REVEL	0.642	indeterminate
SaProt	LLR -12.53	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,988 alleles

Overall 6.84e-05% 1/1,461,838 alleles · very rare

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.Thr57Met
Coding: c.170C>T
MANE Select: NM_001250
dbSNP: rs2515708347
Type: single nucleotide variant
Location: chr20:46122272 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 57: a disulfide bond

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.Thr57= Likely benign ★ 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-thr57met (accessed [today's date]).

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