Is CD40 p.Pro127Ser (c.379C>T) pathogenic?

CD40 p.Pro127Ser (c.379C>T) is classified Uncertain significance in CD40 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1684); Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 3.

What condition is associated with CD40 p.Pro127Ser (c.379C>T)?

CD40 p.Pro127Ser (c.379C>T) is associated with hyper-IgM syndrome type 3 (ClinVar).

How common is CD40 p.Pro127Ser (c.379C>T) in the general population?

CD40 p.Pro127Ser (c.379C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD40 p.Pro127Ser (c.379C>T)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

CD40 p.Pro127Ser

c.379C>T · rs2085343720 · VCV897760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyper-IgM syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign
REVEL	0.499	indeterminate
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.71, phastCons 0.039
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	21.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CD40
Protein: p.Pro127Ser
Coding: c.379C>T
MANE Select: NM_001250
dbSNP: rs2085343720
Type: single nucleotide variant
Location: chr20:46122732 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 127: a disulfide bond

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 p.Pro127= Conflicting classifications of pathogenicity ★ same residue
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

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-pro127ser (accessed [today's date]).

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