Is CARD9 p.Pro99= (c.297G>A) pathogenic?

CARD9 p.Pro99= (c.297G>A) is classified Benign in CARD9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 13.2%, amr) — too common for a highly-penetrant pathogenic allele; Associated with predisposition to invasive fungal disease due to CARD9 deficiency.

What condition is associated with CARD9 p.Pro99= (c.297G>A)?

CARD9 p.Pro99= (c.297G>A) is associated with predisposition to invasive fungal disease due to CARD9 deficiency (ClinVar).

CARD9 p.Pro99=

Q: How common is CARD9 p.Pro99= (c.297G>A) in the general population?

CARD9 p.Pro99= (c.297G>A) is common (popmax 13.2%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.297G>A · rs115131813 · VCV365853

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 13.2%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

predisposition to invasive fungal disease due to CARD9 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.1
Overall
CADD	0.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.2% Admixed American · 7,744/58,456 alleles

Filtering AF 13% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 1.99% 31,935/1,602,174 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	13.2%	8
Remaining individualsnot grpmax-eligible	1.81%	55
European (non-Finnish)	1.8%	56
Finnishnot grpmax-eligible	1.7%	59
Amishnot grpmax-eligible	1.21%	83
African / African-American	0.495%	202
Middle Eastern	0.446%	224
Ashkenazi Jewishnot grpmax-eligible	0.399%	251
South Asian	0.382%	262
East Asian	0.0653%	1,532

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.Pro99=
Coding: c.297G>A
MANE Select: NM_052813
dbSNP: rs115131813
Type: single nucleotide variant
Location: chr9:136371349 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 99: the 'linker' region; a UniProt-annotated variant site (in imd103; reduced cytokine production in response to c.albicans infection; impaired nf-kappa-b transcriptional activity)

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.Pro99Leu Uncertain significance ★★ ⚠ same residue
CARD9 p.Pro99Thr Uncertain significance ★ ⚠ 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

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-pro99 (accessed [today's date]).

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