Is CARD9 p.Leu413Phe (c.1237C>T) pathogenic?

CARD9 p.Leu413Phe (c.1237C>T) is classified Uncertain significance in CARD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-17). AlphaMissense: likely benign (0.1435); Ultra-rare (popmax 0.0268%, eas); Associated with Inborn genetic diseases.

What condition is associated with CARD9 p.Leu413Phe (c.1237C>T)?

CARD9 p.Leu413Phe (c.1237C>T) is associated with Inborn genetic diseases, predisposition to invasive fungal disease due to CARD9 deficiency (ClinVar).

How common is CARD9 p.Leu413Phe (c.1237C>T) in the general population?

CARD9 p.Leu413Phe (c.1237C>T) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about CARD9 p.Leu413Phe (c.1237C>T)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

CARD9 p.Leu413Phe

c.1237C>T · rs752685448 · VCV1004830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 0.45, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	27.2	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 0.0268% East Asian · 12/44,718 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000814% 13/1,597,546 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,727
Remaining individualsnot grpmax-eligible	0.00161%	62,118

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.Leu413Phe
Coding: c.1237C>T
MANE Select: NM_052813
dbSNP: rs752685448
Type: single nucleotide variant
Location: chr9:136367669 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 413: 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.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-leu413phe (accessed [today's date]).

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