Is CD40 p.Pro260Ser (c.778C>T) pathogenic?

CD40 p.Pro260Ser (c.778C>T) is classified Uncertain significance in CD40 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.744); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with CD40 p.Pro260Ser (c.778C>T)?

CD40 p.Pro260Ser (c.778C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CD40 p.Pro260Ser (c.778C>T) in the general population?

CD40 p.Pro260Ser (c.778C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CD40 p.Pro260Ser (c.778C>T)?

AlphaMissense predicts likely pathogenic (score 0.744) — an in-silico prediction, not a clinical call.

CD40 p.Pro260Ser

c.778C>T · rs774515822 · VCV1518597

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.744	likely pathogenic
REVEL	0.324	indeterminate
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 2e-06 · regional, not allelic
Overall
CADD	23.9	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 0.015% Admixed American · 9/60,006 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000805% 13/1,614,068 alleles · ultra-rare exomes 12/1,461,860 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
European (non-Finnish)	0.000339%	295,009

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.Pro260Ser
Coding: c.778C>T
MANE Select: NM_001250
dbSNP: rs774515822
Type: single nucleotide variant
Location: chr20:46128984 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 260: a β-strand; the 'disordered' region

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.Pro260= Likely benign ★ same residue
CD40 p.Ala25Ser Uncertain significance ★★ ⚠ same condition
CD40 p.Ile204Val 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
CD40 p.Thr112Met Uncertain significance ★★ ⚠ same condition
CD40 p.Val138Ala 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-pro260ser (accessed [today's date]).

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