Is CD40 p.Val91Ile (c.271G>A) pathogenic?

CD40 p.Val91Ile (c.271G>A) is classified Uncertain significance in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CD40 p.Val91Ile (c.271G>A)?

CD40 p.Val91Ile (c.271G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CD40 p.Val91Ile (c.271G>A) in the general population?

CD40 p.Val91Ile (c.271G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CD40 p.Val91Ile (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

CD40 p.Val91Ile

c.271G>A · VCV4222915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.19	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 0.93	GERP -0.46, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	11.78	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 0.00223% East Asian · 1/44,876 alleles

Overall 0.000558% 9/1,614,142 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,671
East Asiangrpmax	0.00223%	44,876
Admixed American	0.00167%	60,016
African / African-American	0.00133%	75,020

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val91Ile
Coding: c.271G>A
MANE Select: NM_001250
Type: single nucleotide variant
Location: chr20:46122624 (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.Val91Ala 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-val91ile (accessed [today's date]).

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