Is CD40LG p.Arg181Pro (c.542G>C) pathogenic?

CD40LG p.Arg181Pro (c.542G>C) is classified Conflicting classifications of pathogenicity in CD40LG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1955); Rare (popmax 0.131%, afr); Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Arg181Pro (c.542G>C)?

CD40LG p.Arg181Pro (c.542G>C) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Arg181Pro (c.542G>C) in the general population?

CD40LG p.Arg181Pro (c.542G>C) is rare (popmax 0.131%, afr) (gnomAD).

What do computational predictors say about CD40LG p.Arg181Pro (c.542G>C)?

AlphaMissense predicts likely benign (score 0.1955) — an in-silico prediction, not a clinical call.

CD40LG p.Arg181Pro

c.542G>C · rs11575982 · VCV439470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1955 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1955	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -0.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP -3.3, phastCons 0.43
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	16.47	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

Grpmax group 0.131% African / African-American · 75/57,155 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0985%

Overall 0.00686% 83/1,209,725 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	762
Admixed American	0.00656%	15,253
Remaining individualsnot grpmax-eligible	0.0063%	15,862
European (non-Finnish)	0.000223%	447,471

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.Arg181Pro
Coding: c.542G>C
MANE Select: NM_000074
dbSNP: rs11575982
Type: single nucleotide variant
Location: chrX:136659171 (GRCh38)
Structure: AlphaFold pLDDT 82.34 · 8 PDB
Residue 181: the thd domain; a turn; a disulfide bond

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.Arg181Gln Benign/Likely benign ★★ same residue
CD40LG p.Arg181Trp 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
CD40LG p.Gln174Ter Pathogenic/Likely 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-arg181pro (accessed [today's date]).

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