Is CARD9 p.Asp141His (c.421G>C) pathogenic?

CARD9 p.Asp141His (c.421G>C) is classified Uncertain significance in CARD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.2929); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CARD9 p.Asp141His (c.421G>C)?

CARD9 p.Asp141His (c.421G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CARD9 p.Asp141His (c.421G>C) in the general population?

CARD9 p.Asp141His (c.421G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CARD9 p.Asp141His (c.421G>C)?

AlphaMissense predicts likely benign (score 0.2929) — an in-silico prediction, not a clinical call.

CARD9 p.Asp141His

c.421G>C · VCV3995431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2929	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -12.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,773 bp · p 0.34 · regional, not allelic
Overall
CADD	23.3	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 0.00133% African / African-American · 1/74,940 alleles

Overall 0.000657% 1/152,252 alleles · very rare

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.Asp141His
Coding: c.421G>C
MANE Select: NM_052813
Type: single nucleotide variant
Location: chr9:136371047 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 8 PDB
Residue 141: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CARD9 p.Asp141Asn Uncertain significance ★ ⚠ same residue
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

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-asp141his (accessed [today's date]).

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