Is CARD9 p.Arg188Cys (c.562C>T) pathogenic?

CARD9 p.Arg188Cys (c.562C>T) is classified Uncertain significance in CARD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.1369); Very rare (popmax 0.0033%, sas); Associated with predisposition to invasive fungal disease due to CARD9 deficiency.

What condition is associated with CARD9 p.Arg188Cys (c.562C>T)?

CARD9 p.Arg188Cys (c.562C>T) is associated with predisposition to invasive fungal disease due to CARD9 deficiency (ClinVar).

How common is CARD9 p.Arg188Cys (c.562C>T) in the general population?

CARD9 p.Arg188Cys (c.562C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about CARD9 p.Arg188Cys (c.562C>T)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

CARD9 p.Arg188Cys

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.562C>T · VCV4704276

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

predisposition to invasive fungal disease due to CARD9 deficiency

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -9.80	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 5.6	GERP 0.52, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	24.4	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 0.0033% South Asian · 3/91,026 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000621% 10/1,611,086 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,342
Remaining individualsnot grpmax-eligible	0.0016%	62,366
European (non-Finnish)	0.000509%	196,482

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.Arg188Cys
Coding: c.562C>T
MANE Select: NM_052813
Type: single nucleotide variant
Location: chr9:136370906 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 188: 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); an α-helix

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-arg188cys (accessed [today's date]).

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