Is CARD9 p.Arg342Cys (c.1024C>T) pathogenic?

CARD9 p.Arg342Cys (c.1024C>T) is classified Uncertain significance in CARD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: ambiguous (0.4331); Very rare (popmax 0.00167%, amr); Associated with predisposition to invasive fungal disease due to CARD9 deficiency.

What condition is associated with CARD9 p.Arg342Cys (c.1024C>T)?

CARD9 p.Arg342Cys (c.1024C>T) is associated with predisposition to invasive fungal disease due to CARD9 deficiency (ClinVar).

How common is CARD9 p.Arg342Cys (c.1024C>T) in the general population?

CARD9 p.Arg342Cys (c.1024C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CARD9 p.Arg342Cys (c.1024C>T)?

AlphaMissense predicts ambiguous (score 0.4331) — an in-silico prediction, not a clinical call.

CARD9 p.Arg342Cys

Q: How is Predisposition to invasive fungal disease due to CARD9 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1024C>T · rs1286367809 · VCV1499680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

predisposition to invasive fungal disease due to CARD9 deficiency

Computational evidence

Protein change
AlphaMissense	0.4331	ambiguous
REVEL	0.526	indeterminate
SaProt	LLR -11.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	31.0	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 0.00167% Admixed American · 1/59,958 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,612,428 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,958
European (non-Finnish)	0.000593%	168,556

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.Arg342Cys
Coding: c.1024C>T
MANE Select: NM_052813
dbSNP: rs1286367809
Type: single nucleotide variant
Location: chr9:136369803 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 342: 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

predisposition to invasive fungal disease due to CARD9 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Predisposition to invasive fungal disease due to CARD9 deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

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
CARD9 p.Ala290Val 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-arg342cys (accessed [today's date]).

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