Is CARD9 p.Cys402Arg (c.1204T>C) pathogenic?

CARD9 p.Cys402Arg (c.1204T>C) is classified Likely benign in CARD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely benign (0.0463); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CARD9 p.Cys402Arg (c.1204T>C)?

CARD9 p.Cys402Arg (c.1204T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CARD9 p.Cys402Arg (c.1204T>C) in the general population?

CARD9 p.Cys402Arg (c.1204T>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about CARD9 p.Cys402Arg (c.1204T>C)?

AlphaMissense predicts likely benign (score 0.0463) — an in-silico prediction, not a clinical call.

CARD9 p.Cys402Arg

c.1204T>C · rs773952828 · VCV2390310

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0463	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -3.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.86	GERP -3.4
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	0.26	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 0.00271% European (non-Finnish) · 32/1,179,010 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00231% 37/1,603,220 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,144
European (non-Finnish)grpmax	0.00271%	36,844
Admixed American	0.00167%	59,800
African / African-American	0.00134%	74,882
South Asian	0.00111%	90,422

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys402Arg
Coding: c.1204T>C
MANE Select: NM_052813
dbSNP: rs773952828
Type: single nucleotide variant
Location: chr9:136367702 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 402: 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

Similar variants

CARD9 p.Ala109Val Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala190Val Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala198Thr Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala369Thr Uncertain significance ★★ ⚠ same condition
CARD9 p.Ala392Val Uncertain significance ★★ ⚠ same condition
CARD9 p.Arg173Cys Uncertain significance ★★ ⚠ same condition
CARD9 p.Arg241Trp Uncertain significance ★★ ⚠ same condition
CARD9 p.Arg315Leu 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-cys402arg (accessed [today's date]).

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