Is CARD11 p.Arg47Ser (c.139C>A) pathogenic?

CARD11 p.Arg47Ser (c.139C>A) is classified Uncertain significance in CARD11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with severe combined immunodeficiency due to CARD11 deficiency.

What condition is associated with CARD11 p.Arg47Ser (c.139C>A)?

CARD11 p.Arg47Ser (c.139C>A) is associated with severe combined immunodeficiency due to CARD11 deficiency, BENTA disease (ClinVar).

How common is CARD11 p.Arg47Ser (c.139C>A) in the general population?

CARD11 p.Arg47Ser (c.139C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CARD11 p.Arg47Ser (c.139C>A)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CARD11 p.Arg47Ser

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.139C>A · rs1780507453 · VCV1514395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe combined immunodeficiency due to CARD11 deficiency

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 1% in CARD11
REVEL	0.612	indeterminate
SaProt	LLR -14.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,248 bp · p 4.5e-20 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Arg47Ser
Coding: c.139C>A
MANE Select: NM_032415
dbSNP: rs1780507453
Type: single nucleotide variant
Location: chr7:2947656 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 2 PDB
Residue 47: 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.Arg47His Pathogenic/Likely pathogenic ★★ same residue
CARD11 p.Arg47Cys Uncertain significance ★ ⚠ same residue
CARD11 p.Arg30Trp 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-arg47ser (accessed [today's date]).

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