Is CARD11 p.Arg235Gln (c.704G>A) pathogenic?

CARD11 p.Arg235Gln (c.704G>A) is classified Uncertain significance in CARD11 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-04). AlphaMissense: likely benign (0.1262); Very rare (popmax 0.00667%, amr); Associated with CARD11-related disorder.

What condition is associated with CARD11 p.Arg235Gln (c.704G>A)?

CARD11 p.Arg235Gln (c.704G>A) is associated with CARD11-related disorder, severe combined immunodeficiency due to CARD11 deficiency, BENTA disease (ClinVar).

How common is CARD11 p.Arg235Gln (c.704G>A) in the general population?

CARD11 p.Arg235Gln (c.704G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CARD11 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts likely benign (score 0.1262) — an in-silico prediction, not a clinical call.

CARD11 p.Arg235Gln

c.704G>A · rs148083162 · VCV1022746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CARD11-related disorder

Computational evidence

Protein change
AlphaMissense	0.1262	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 4,668 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	23.8	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 0.00667% Admixed American · 4/60,008 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00465% 75/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	0.00559%	17,879
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,870
African / African-American	0.00134%	74,900

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.Arg235Gln
Coding: c.704G>A
MANE Select: NM_032415
dbSNP: rs148083162
Type: single nucleotide variant
Location: chr7:2939909 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 2 PDB

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

Disease context

CARD11-related disorder

Also linked: severe combined immunodeficiency due to CARD11 deficiency BENTA disease

Similar variants

CARD11 p.Arg235= Likely benign ★★ same residue
CARD11 p.Arg235Trp 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

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-arg235gln (accessed [today's date]).

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