Is CD40 p.Glu144Lys (c.430G>A) pathogenic?

CD40 p.Glu144Lys (c.430G>A) is classified Likely pathogenic in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). AlphaMissense: likely benign (0.1265); Very rare (popmax 0.00167%, amr); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Glu144Lys (c.430G>A)?

CD40 p.Glu144Lys (c.430G>A) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Glu144Lys (c.430G>A) in the general population?

CD40 p.Glu144Lys (c.430G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CD40 p.Glu144Lys (c.430G>A)?

AlphaMissense predicts likely benign (score 0.1265) — an in-silico prediction, not a clinical call.

CD40 p.Glu144Lys

c.430G>A · VCV3629833

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.1265	likely benign ⚠ discordant with ClinVar
REVEL	0.094	moderately benign-leaning
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -3.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	16.12	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 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00133%	74,918
European (non-Finnish)	0.000254%	393,342

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.Glu144Lys
Coding: c.430G>A
MANE Select: NM_001250
Type: single nucleotide variant
Location: chr20:46123152 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 144: a β-strand

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.Glu144Gln 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-glu144lys (accessed [today's date]).

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