Is CD40 p.Ala207= (c.621C>T) pathogenic?

CD40 p.Ala207= (c.621C>T) is classified Benign/Likely benign in CD40 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Rare (popmax 0.762%, sas); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Ala207= (c.621C>T)?

CD40 p.Ala207= (c.621C>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Ala207= (c.621C>T) in the general population?

CD40 p.Ala207= (c.621C>T) is rare (popmax 0.762%, sas) (gnomAD).

CD40 p.Ala207=

c.621C>T · rs535886332 · VCV897762

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.762%, sas)

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.062	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -0.43
Overall
CADD	1.485	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.762% South Asian · 694/91,044 alleles

Filtering AF 0.715% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.696%

Overall 0.0456% 736/1,613,544 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.762%	131
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0528%	1,894
African / African-American	0.00267%	37,411
European (non-Finnish)	0.000254%	393,303

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: CD40
Protein: p.Ala207=
Coding: c.621C>T
MANE Select: NM_001250
dbSNP: rs535886332
Type: single nucleotide variant
Location: chr20:46128199 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB

Full CD40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyper-IgM syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD40 c.*178G>A Uncertain significance ★★ same condition
CD40 c.*547A>T Uncertain significance ★★ same condition
CD40 c.403+20A>G Benign/Likely benign ★★ same condition
CD40 c.52-15C>T Benign/Likely benign ★★ same condition
CD40 c.559+36G>C Benign ★★ same condition
CD40 c.-1T>C Benign/Likely benign ★★ same condition
CD40 c.*135C>G Benign ★★ same condition
CD40 c.*316G>C Benign ★★ 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/cd40-p-ala207 (accessed [today's date]).

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