Is CD40 p.Val91Ala (c.272T>C) pathogenic?

CD40 p.Val91Ala (c.272T>C) is classified Uncertain significance in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.2646); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with CD40 p.Val91Ala (c.272T>C)?

CD40 p.Val91Ala (c.272T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CD40 p.Val91Ala (c.272T>C) in the general population?

CD40 p.Val91Ala (c.272T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CD40 p.Val91Ala (c.272T>C)?

AlphaMissense predicts likely benign (score 0.2646) — an in-silico prediction, not a clinical call.

CD40 p.Val91Ala

c.272T>C · rs750063104 · VCV2290696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2646	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -9.26	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 5.8	GERP 0.68, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,050 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,894 alleles · very rare

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.Val91Ala
Coding: c.272T>C
MANE Select: NM_001250
dbSNP: rs750063104
Type: single nucleotide variant
Location: chr20:46122625 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 91: a disulfide bond; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD40 p.Val91Ile Uncertain significance ★ ⚠ same residue
CD40 p.Val91= Likely benign ★ same residue
CD40 p.Ala25Ser Uncertain significance ★★ ⚠ same condition
CD40 p.Ile204Val Uncertain significance ★★ ⚠ same condition
CD40 p.Pro260Ser Uncertain significance ★★ ⚠ same condition
CD40 p.Ser245Cys Uncertain significance ★★ ⚠ same condition
CD40 p.Ser245Phe Uncertain significance ★★ ⚠ same condition
CD40 p.Thr112Lys Uncertain significance ★★ ⚠ 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-val91ala (accessed [today's date]).

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