Is CD40 p.Thr136Ala (c.406A>G) pathogenic?

CD40 p.Thr136Ala (c.406A>G) is classified Uncertain significance in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-06). AlphaMissense: likely benign (0.1316); Very rare (popmax 8.48e-05%, nfe).

How common is CD40 p.Thr136Ala (c.406A>G) in the general population?

CD40 p.Thr136Ala (c.406A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CD40 p.Thr136Ala (c.406A>G)?

AlphaMissense predicts likely benign (score 0.1316) — an in-silico prediction, not a clinical call.

CD40 p.Thr136Ala

c.406A>G · VCV3632747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1316	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -12.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	20.4	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 8.48e-05% European (non-Finnish) · 1/1,179,160 alleles

Overall 6.2e-05% 1/1,613,228 alleles · very rare exomes 1/1,460,934 · genomes 0/152,294 · joint denominator

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.Thr136Ala
Coding: c.406A>G
MANE Select: NM_001250
Type: single nucleotide variant
Location: chr20:46123128 (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

Similar variants

CD40 p.Thr136= Pathogenic 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-thr136ala (accessed [today's date]).

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