Is CD40 p.Ile208Val (c.622A>G) pathogenic?

CD40 p.Ile208Val (c.622A>G) is classified Conflicting classifications of pathogenicity in CD40 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0662); Rare (popmax 0.825%, eas); Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Ile208Val (c.622A>G)?

CD40 p.Ile208Val (c.622A>G) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Ile208Val (c.622A>G) in the general population?

CD40 p.Ile208Val (c.622A>G) is rare (popmax 0.825%, eas) (gnomAD).

What do computational predictors say about CD40 p.Ile208Val (c.622A>G)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

CD40 p.Ile208Val

c.622A>G · rs199581355 · VCV898906

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.825%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -5.26	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 -1.5	GERP -3.7
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	0.26	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 0.825% East Asian · 369/44,744 alleles

Filtering AF 0.755% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.728%

Overall 0.0232% 374/1,612,058 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.825%	121
Remaining individualsnot grpmax-eligible	0.008%	12,493

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.Ile208Val
Coding: c.622A>G
MANE Select: NM_001250
dbSNP: rs199581355
Type: single nucleotide variant
Location: chr20:46128200 (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-ile208val (accessed [today's date]).

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