Is CD40LG p.Val126Phe (c.376G>T) pathogenic?

CD40LG p.Val126Phe (c.376G>T) is classified Uncertain significance in CD40LG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-02). AlphaMissense: ambiguous (0.4013); Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Val126Phe (c.376G>T)?

CD40LG p.Val126Phe (c.376G>T) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Val126Phe (c.376G>T) in the general population?

CD40LG p.Val126Phe (c.376G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD40LG p.Val126Phe (c.376G>T)?

AlphaMissense predicts ambiguous (score 0.4013) — an in-silico prediction, not a clinical call.

CD40LG p.Val126Phe

c.376G>T · rs2148552915 · VCV1438322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4013 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.4013	ambiguous
REVEL	0.654	pathogenic-leaning
SaProt	LLR -8.78	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.86, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	21.1	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

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.Val126Phe
Coding: c.376G>T
MANE Select: NM_000074
dbSNP: rs2148552915
Type: single nucleotide variant
Location: chrX:136656385 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB
Residue 126: 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 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.Gln174Ter Pathogenic/Likely pathogenic ★★ same condition
CD40LG p.Gln220Ter Pathogenic ★★ same condition
CD40LG p.Gln90Ter 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-val126phe (accessed [today's date]).

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