Is CARD9 p.Pro432Ser (c.1294C>T) pathogenic?

CARD9 p.Pro432Ser (c.1294C>T) is classified Uncertain significance in CARD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-03). AlphaMissense: likely benign (0.0912); Ultra-rare (popmax 0.0484%, amr); Associated with Inborn genetic diseases.

What condition is associated with CARD9 p.Pro432Ser (c.1294C>T)?

CARD9 p.Pro432Ser (c.1294C>T) is associated with Inborn genetic diseases, predisposition to invasive fungal disease due to CARD9 deficiency (ClinVar).

How common is CARD9 p.Pro432Ser (c.1294C>T) in the general population?

CARD9 p.Pro432Ser (c.1294C>T) is ultra-rare (popmax 0.0484%, amr) (gnomAD).

What do computational predictors say about CARD9 p.Pro432Ser (c.1294C>T)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

CARD9 p.Pro432Ser

c.1294C>T · rs781498143 · VCV1441210

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.09	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 9.4	GERP 1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	20.3	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 0.0484% Admixed American · 29/59,968 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00316% 51/1,612,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0484%	2,068
Remaining individualsnot grpmax-eligible	0.0112%	8,923
African / African-American	0.00133%	74,942
European (non-Finnish)	0.00119%	84,277

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: CARD9
Protein: p.Pro432Ser
Coding: c.1294C>T
MANE Select: NM_052813
dbSNP: rs781498143
Type: single nucleotide variant
Location: chr9:136367233 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 432: the 'disordered' region; a UniProt-annotated variant site (in imd103; reduced cytokine production in response to c.albicans infection; impaired nf-kappa-b transcriptional activity); a UniProt-annotated variant site (in imd103; decreased production of cytokines in cd4(+) th17 cells); a UniProt-annotated variant site (in imd103; reduced production igg antibodies in response to c.albicans infection); a UniProt-annotated variant site (in imd103; reduced cytokine production in response to c.albicans infection)

Full CARD9 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

Also linked: predisposition to invasive fungal disease due to CARD9 deficiency

Similar variants

CARD9 p.Pro432= Likely benign ★ same residue
CARD9 p.Gln289Ter Pathogenic ★★ same condition
CARD9 p.Gln295Ter Pathogenic ★★ same condition
CARD9 c.-126C>A Uncertain significance ★★ same condition
CARD9 p.Ala109Val Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala190Val Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala198Thr Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala199Val 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/card9-p-pro432ser (accessed [today's date]).

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