Is CARD11 p.Arg35Cys (c.103C>T) pathogenic?

CARD11 p.Arg35Cys (c.103C>T) is classified Uncertain significance in CARD11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: ambiguous (0.5322); Absent from gnomAD v4.1; Associated with severe combined immunodeficiency due to CARD11 deficiency.

What condition is associated with CARD11 p.Arg35Cys (c.103C>T)?

CARD11 p.Arg35Cys (c.103C>T) is associated with severe combined immunodeficiency due to CARD11 deficiency, BENTA disease (ClinVar).

How common is CARD11 p.Arg35Cys (c.103C>T) in the general population?

CARD11 p.Arg35Cys (c.103C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CARD11 p.Arg35Cys (c.103C>T)?

AlphaMissense predicts ambiguous (score 0.5322) — an in-silico prediction, not a clinical call.

CARD11 p.Arg35Cys

Q: How is Combined immunodeficiency due to CARD11 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.103C>T · rs1780508141 · VCV1003822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5322 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

severe combined immunodeficiency due to CARD11 deficiency

Computational evidence

Protein change
AlphaMissense	0.5322	ambiguous
REVEL	0.583	indeterminate
SaProt	LLR -10.16	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,248 bp · p 4.5e-20 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CARD11
Protein: p.Arg35Cys
Coding: c.103C>T
MANE Select: NM_032415
dbSNP: rs1780508141
Type: single nucleotide variant
Location: chr7:2947692 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 2 PDB
Residue 35: the card domain; an α-helix

Full CARD11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency due to CARD11 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BENTA disease

For Combined immunodeficiency due to CARD11 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CARD11 p.Arg35Gly Uncertain significance ★ same residue
CARD11 p.Arg30Trp Pathogenic/Likely pathogenic ★★ same condition
CARD11 p.Arg47His Pathogenic/Likely pathogenic ★★ same condition
CARD11 p.Arg837Ter Pathogenic ★★ same condition
CARD11 p.Gly123Asp Pathogenic ★★ ⚠ same condition
CARD11 p.Gly123Ser Pathogenic ★★ ⚠ same condition
CARD11 c.1807+5G>A Uncertain significance ★★ same condition
CARD11 c.2269+3G>A 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/card11-p-arg35cys (accessed [today's date]).

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