Is CD40LG p.Gln174Ter (c.520C>T) pathogenic?

CD40LG p.Gln174Ter (c.520C>T) is classified Pathogenic/Likely pathogenic in CD40LG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-28). Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Gln174Ter (c.520C>T)?

CD40LG p.Gln174Ter (c.520C>T) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Gln174Ter (c.520C>T) in the general population?

CD40LG p.Gln174Ter (c.520C>T) is absent from gnomAD v4.1 (gnomAD).

CD40LG p.Gln174Ter

c.520C>T · rs1603321772 · VCV650284

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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: CD40LG
Protein: p.Gln174Ter
Coding: c.520C>T
MANE Select: NM_000074
dbSNP: rs1603321772
Type: single nucleotide variant
Location: chrX:136659149 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB
Residue 174: a UniProt-annotated variant site (in higm1; decreases itga5:itgb1 and itgav:itgb3 binding of the soluble form; decreases activation of nf-kappa-b signaling); the thd domain; a β-strand

Full CD40LG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyper-IgM syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD40LG c.346+5G>A Pathogenic/Likely pathogenic ★★ same condition
CD40LG c.347-2A>G Pathogenic ★★ same condition
CD40LG p.Arg11Ter Pathogenic ★★ same condition
CD40LG p.Cys218Ter Pathogenic ★★ same condition
CD40LG p.Gln160Ter Pathogenic ★★ same condition
CD40LG p.Gln220Ter Pathogenic ★★ same condition
CD40LG p.Gln90Ter Pathogenic ★★ same condition
CD40LG p.Glu56Ter Pathogenic ★★ 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/cd40lg-p-gln174ter (accessed [today's date]).

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