Is CARD11 p.Pro554del (c.1661_1663del) pathogenic?

CARD11 p.Pro554del (c.16611663del) is classified Uncertain significance in CARD11 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-10). Very rare (popmax 0.00988%, sas); Associated with severe combined immunodeficiency due to CARD11 deficiency.

What condition is associated with CARD11 p.Pro554del (c.1661_1663del)?

CARD11 p.Pro554del (c.1661_1663del) is associated with severe combined immunodeficiency due to CARD11 deficiency, BENTA disease (ClinVar).

How common is CARD11 p.Pro554del (c.1661_1663del) in the general population?

CARD11 p.Pro554del (c.1661_1663del) is very rare (popmax 0.00988%, sas) (gnomAD).

CARD11 p.Pro554del

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.1661_1663del · rs762770988 · VCV2954180

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Conditions

severe combined immunodeficiency due to CARD11 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Overall
CADD	16.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,054 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000993% 16/1,611,368 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,117
East Asian	0.00223%	44,884
European (non-Finnish)	0.000509%	196,640

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: CARD11
Protein: p.Pro554del
Coding: c.1661_1663del
MANE Select: NM_032415
dbSNP: rs762770988
Type: Deletion
Location: chr7:2928689 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 2 PDB
Residue 554: the 'inhibitory domain (id)' region; the 'disordered' region

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.Pro554Arg Uncertain significance ★ ⚠ same residue
CARD11 p.Pro554His Uncertain significance ★ ⚠ same residue
CARD11 p.Pro554= Likely benign ★ same residue
CARD11 c.1755-20del Benign/Likely benign ★★ same condition
CARD11 p.Arg555fs Pathogenic ★ same condition
CARD11 p.Arg888fs Pathogenic ★ same condition
CARD11 p.Gly860fs Pathogenic ★ same condition
CARD11 p.Leu267fs Pathogenic ★ 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-pro554del (accessed [today's date]).

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