Is CD40 p.Ala115Val (c.344C>T) pathogenic?

CD40 p.Ala115Val (c.344C>T) is classified Uncertain significance in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-25). AlphaMissense: likely benign (0.1042); Ultra-rare (popmax 0.0333%, amr).

How common is CD40 p.Ala115Val (c.344C>T) in the general population?

CD40 p.Ala115Val (c.344C>T) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about CD40 p.Ala115Val (c.344C>T)?

AlphaMissense predicts likely benign (score 0.1042) — an in-silico prediction, not a clinical call.

CD40 p.Ala115Val

c.344C>T · rs537489349 · VCV1362871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1042 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1042	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.56	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 0.029	GERP -1.4
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	8.818	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 0.0333% Admixed American · 20/59,994 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00192% 31/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00401%	24,965

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.Ala115Val
Coding: c.344C>T
MANE Select: NM_001250
dbSNP: rs537489349
Type: single nucleotide variant
Location: chr20:46122697 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 115: a disulfide bond

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

Similar variants

CD40 p.Ala115Asp Uncertain significance ★ ⚠ same residue
CD40 c.256+5G>A Uncertain significance ★★ same type
CD40 c.*178G>A Uncertain significance ★★ same type
CD40 c.*547A>T Uncertain significance ★★ same type
CD40 p.Ala25Ser Uncertain significance ★★ ⚠ same type
CD40 p.Arg123His Uncertain significance ★★ ⚠ same type
CD40 p.Asn180Lys Uncertain significance ★★ ⚠ same type
CD40 p.Glu159Lys Uncertain significance ★★ ⚠ same type

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-ala115val (accessed [today's date]).

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