Is CD40LG p.Phe229Ser (c.686T>C) pathogenic?

CD40LG p.Phe229Ser (c.686T>C) is classified Conflicting classifications of pathogenicity in CD40LG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-09). AlphaMissense: likely pathogenic (0.921); Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Phe229Ser (c.686T>C)?

CD40LG p.Phe229Ser (c.686T>C) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Phe229Ser (c.686T>C) in the general population?

CD40LG p.Phe229Ser (c.686T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD40LG p.Phe229Ser (c.686T>C)?

AlphaMissense predicts likely pathogenic (score 0.921) — an in-silico prediction, not a clinical call.

CD40LG p.Phe229Ser

c.686T>C · rs1569377865 · VCV624445

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.921	likely pathogenic · top 5% in CD40LG
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -10.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	25.9	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.Phe229Ser
Coding: c.686T>C
MANE Select: NM_000074
dbSNP: rs1569377865
Type: single nucleotide variant
Location: chrX:136659315 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB
Residue 229: 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 p.Phe229Leu Conflicting classifications of pathogenicity ★ ⚠ 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
CD40LG p.Gln174Ter Pathogenic/Likely pathogenic ★★ same condition
CD40LG p.Gln220Ter 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-phe229ser (accessed [today's date]).

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