Is CD40LG p.Ser9Phe (c.26C>T) pathogenic?

CD40LG p.Ser9Phe (c.26C>T) is classified Uncertain significance in CD40LG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely benign (0.1483); Very rare (popmax 0.00113%, nfe); Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Ser9Phe (c.26C>T)?

CD40LG p.Ser9Phe (c.26C>T) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Ser9Phe (c.26C>T) in the general population?

CD40LG p.Ser9Phe (c.26C>T) is very rare (popmax 0.00113%, nfe) (gnomAD).

What do computational predictors say about CD40LG p.Ser9Phe (c.26C>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

CD40LG p.Ser9Phe

c.26C>T · rs1338696512 · VCV860054

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.85, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	19.22	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00113% European (non-Finnish) · 10/888,888 alleles

Filtering AF 0.000569% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000415%

Overall 0.000832% 10/1,202,489 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: CD40LG
Protein: p.Ser9Phe
Coding: c.26C>T
MANE Select: NM_000074
dbSNP: rs1338696512
Type: single nucleotide variant
Location: chrX:136648274 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB

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-ser9phe (accessed [today's date]).

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