Is CD40 p.Phe158= (c.474C>T) pathogenic?

CD40 p.Phe158= (c.474C>T) is classified Likely benign in CD40 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). Very rare (popmax 0.01%, amr).

How common is CD40 p.Phe158= (c.474C>T) in the general population?

CD40 p.Phe158= (c.474C>T) is very rare (popmax 0.01%, amr) (gnomAD).

CD40 p.Phe158=

c.474C>T · rs79661585 · VCV632740

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.4	GERP -4.1
Overall
CADD	0.773	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,006 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00192% 31/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
African / African-American	0.00667%	14,986
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00153%	65,551
South Asian	0.0011%	91,090

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.Phe158=
Coding: c.474C>T
MANE Select: NM_001250
dbSNP: rs79661585
Type: single nucleotide variant
Location: chr20:46123196 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 81.10 · 14 PDB
Residue 158: a β-strand

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

Similar variants

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
CD40 p.Ile204Val 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-phe158 (accessed [today's date]).

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