# NM_032415.7(CARD11):c.1485G>A (p.Pro495=)

https://sugi.bio/variant/card11-p-pro495

## Summary

**CARD11 p.Pro495= (c.1485G>A)** is classified **Likely benign** in CARD11 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). Very rare (popmax 0.00551%, nfe); Associated with severe combined immunodeficiency due to CARD11 deficiency.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs375570275 · 3 submitters · 2 linked conditions · very rare (popmax 0.00551%, nfe)

## For patients & families {#patients}

This is a change in the CARD11 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to severe combined immunodeficiency due to CARD11 deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CARD11 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017549/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CARD11](https://sugi.bio/atlas/gene/CARD11/) |
| Protein change (HGVS p.) | p.Pro495= |
| Coding change (HGVS c.) | c.1485G>A |
| MANE Select transcript | [NM_032415](https://www.ncbi.nlm.nih.gov/nuccore/NM_032415) |
| dbSNP | [rs375570275](https://www.ncbi.nlm.nih.gov/snp/rs375570275/) |
| Variant type | single nucleotide variant |
| Location | chr7:2934486-2934486 (GRCh38) |
| ClinVar | [VCV1109861](https://www.ncbi.nlm.nih.gov/clinvar/variation/1109861/) |

**All HGVS expressions:** `LRG_729:g.114390G>A`, `LRG_729t1:c.1485G>A`, `LRG_729t2:c.1485G>A`, `NC_000007.13:g.2974120C>T`, `NC_000007.14:g.2934486C>T`, `NG_027759.1:g.114390G>A`, `NM_001324281.3:c.1485G>A`, `NM_032415.5:c.1485G>A`, `NM_032415.7:c.1485G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -14.239, GERP -3.86 — fast-evolving / accelerated position
- CADD: **PHRED 0.119**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.44 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00551%** (nfe) · FAF95 0.00443% · FAF99 0.00403% · 65/1,179,966 in the highest group · 71/1,613,900 alleles overall — very rare (popmax 0.00551%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00551% | 18,153 |
| Finnish (not grpmax-eligible) | 0.00468% | 21,346 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| African / African-American | 0.00133% | 74,928 |
| South Asian | 0.0011% | 91,040 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CARD11** population constraint: LOEUF 0.364, pLI 1, missense-Z 3.7309. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **BENTA disease** — Definitive (AD)
- **severe combined immunodeficiency due to CARD11 deficiency** — Definitive (AR)
- **immunodeficiency 11b with atopic dermatitis** — Definitive (AD)

## Protein context {#protein}

Residue **495** lies in the 'inhibitory domain (id)' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 71.83, 26% of residues very-high.

**2 experimental structure(s)** (PDB): [4JUP](https://www.rcsb.org/structure/4JUP), [4LWD](https://www.rcsb.org/structure/4LWD).

## What this gene does {#gene-function}

*Describes the biological roles of CARD11 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CARD11's established molecular role includes CARD domain binding. p.Pro495= falls in the inhibitory domain (id) region.


### Pathways affected {#pathways}

CARD11 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | electronic |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** CARD domain binding.

**Biological process:** canonical NF-kappaB signal transduction, T cell costimulation, positive regulation of interleukin-2 production, TORC1 signaling, positive regulation of canonical NF-kappaB signal transduction, positive regulation of T cell receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing | 2022-06-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-01 |

## Associated conditions {#conditions}

[severe combined immunodeficiency due to CARD11 deficiency](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency-due-to-card11-deficiency/), [BENTA disease](https://sugi.bio/atlas/disease/benta-disease/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency due to CARD11 deficiency, BENTA disease, not specified, not provided, Immunodeficiency 11, IMMUNODEFICIENCY 11A, B-cell expansion with NFKB and T-cell anergy, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CARD11 variant pages (same residue, condition, or type): [CARD11 p.Pro495Leu](/variant/card11-p-pro495leu), [CARD11 p.Arg30Trp](/variant/card11-p-arg30trp), [CARD11 p.Arg47His](/variant/card11-p-arg47his), [CARD11 p.Arg837Ter](/variant/card11-p-arg837ter), [CARD11 p.Gly123Asp](/variant/card11-p-gly123asp), [CARD11 p.Gly123Ser](/variant/card11-p-gly123ser), [CARD11 c.1807+5G>A](/variant/card11-c-1807-plus-5g-a), [CARD11 c.2269+3G>A](/variant/card11-c-2269-plus-3g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1109861). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*