Is CD40LG p.Val64Ala (c.191T>C) pathogenic?

CD40LG p.Val64Ala (c.191T>C) is classified Benign in CD40LG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-28). AlphaMissense: ambiguous (0.3619); Ultra-rare (popmax 0.0232%, sas); Associated with hyper-IgM syndrome type 1.

What condition is associated with CD40LG p.Val64Ala (c.191T>C)?

CD40LG p.Val64Ala (c.191T>C) is associated with hyper-IgM syndrome type 1 (ClinVar).

How common is CD40LG p.Val64Ala (c.191T>C) in the general population?

CD40LG p.Val64Ala (c.191T>C) is ultra-rare (popmax 0.0232%, sas) (gnomAD).

What do computational predictors say about CD40LG p.Val64Ala (c.191T>C)?

AlphaMissense predicts ambiguous (score 0.3619) — an in-silico prediction, not a clinical call.

CD40LG p.Val64Ala

c.191T>C · rs771501540 · VCV2976625

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, sas)

Conditions

hyper-IgM syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.3619	ambiguous
REVEL	0.382	indeterminate
SaProt	LLR -5.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	22.7	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 0.0232% South Asian · 13/56,152 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.00127% 15/1,182,751 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0232%	4,319
Remaining individualsnot grpmax-eligible	0.00429%	23,316

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.Val64Ala
Coding: c.191T>C
MANE Select: NM_000074
dbSNP: rs771501540
Type: single nucleotide variant
Location: chrX:136650300 (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 p.Val64fs Pathogenic 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-val64ala (accessed [today's date]).

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