Is CD40LG p.Glu129Ter (c.385G>T) pathogenic?

CD40LG p.Glu129Ter (c.385G>T) is classified Pathogenic in CD40LG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Glu129Ter (c.385G>T)?

CD40LG p.Glu129Ter (c.385G>T) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Glu129Ter (c.385G>T) in the general population?

CD40LG p.Glu129Ter (c.385G>T) is absent from gnomAD v4.1 (gnomAD).

CD40LG p.Glu129Ter

c.385G>T · rs1215852570 · VCV1405864

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (4 of 5, 24 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.22	donor loss · deltas
Pangolin	Δ0.20	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.1	GERP 0.86, phastCons 1
Overall
CADD	37.0	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.Glu129Ter
Coding: c.385G>T
MANE Select: NM_000074
dbSNP: rs1215852570
Type: single nucleotide variant
Location: chrX:136656394 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB
Residue 129: a UniProt-annotated variant site (in higm1); a β-strand; the thd domain

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 p.Glu129= Likely benign ★ same residue
CD40LG p.Glu129fs Pathogenic ★ same residue
CD40LG p.Glu129Lys Uncertain significance ★ same residue
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

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-glu129ter (accessed [today's date]).

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