Is CD40LG p.Arg181Gln (c.542G>A) pathogenic?

CD40LG p.Arg181Gln (c.542G>A) is classified Benign/Likely benign in CD40LG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0735); Low-frequency (popmax 1.48%, sas); Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Arg181Gln (c.542G>A)?

CD40LG p.Arg181Gln (c.542G>A) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Arg181Gln (c.542G>A) in the general population?

CD40LG p.Arg181Gln (c.542G>A) is low-frequency (popmax 1.48%, sas) (gnomAD).

What do computational predictors say about CD40LG p.Arg181Gln (c.542G>A)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

CD40LG p.Arg181Gln

c.542G>A · rs11575982 · VCV530672

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.48%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -4.42	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 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	11.05	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 1.48% South Asian · 839/56,808 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.36%

Overall 0.0829% 1,003/1,209,778 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.48%	68
Remaining individualsnot grpmax-eligible	0.155%	643
East Asian	0.154%	649
Middle Eastern	0.115%	871
Admixed American	0.00437%	22,886
African / African-American	0.0035%	28,612
European (non-Finnish)	0.00324%	30,860

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.Arg181Gln
Coding: c.542G>A
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.Arg181Pro Conflicting classifications of pathogenicity ★ ⚠ 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-arg181gln (accessed [today's date]).

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