# NM_001184900.3(CARD8):c.786C>T (p.Asp262=)

https://sugi.bio/variant/card8-p-asp262

## Summary

**CARD8 p.Asp262= (c.786C>T)** is classified **Likely benign** in CARD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). Very rare (popmax 0.00329%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the CARD8 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CARD8](https://sugi.bio/atlas/gene/CARD8/) |
| Protein change (HGVS p.) | p.Asp262= |
| Coding change (HGVS c.) | c.786C>T |
| MANE Select transcript | [NM_001184900](https://www.ncbi.nlm.nih.gov/nuccore/NM_001184900) |
| Variant type | single nucleotide variant |
| Location | chr19:48230687-48230687 (GRCh38) |
| ClinVar | [VCV3603715](https://www.ncbi.nlm.nih.gov/clinvar/variation/3603715/) |

**All HGVS expressions:** `NC_000019.10:g.48230687G>A`, `NC_000019.9:g.48733944G>A`, `NG_029574.2:g.30583C>T`, `NG_029574.3:g.30259C>T`, `NM_001184900.3:c.786C>T`, `NM_001184901.1:c.636C>T`, `NM_001184902.2:c.786C>T`, `NM_001184903.1:c.786C>T`, `NM_001351782.2:c.786C>T`, `NM_001351783.2:c.636C>T`, `NM_001351784.2:c.471C>T`, `NM_001351786.2:c.450C>T`, `NM_001351787.2:c.471C>T`, `NM_001351788.2:c.636C>T`, `NM_001351789.2:c.636C>T`, `NM_001351790.2:c.543C>T`, `NM_001351791.2:c.471C>T`, `NM_001351792.2:c.471C>T`, `NM_001365950.1:c.468C>T`, `NM_014959.5:c.636C>T`, `NR_033678.1:n.746C>T`, `NR_033679.1:n.788C>T`, `NR_033680.1:n.746C>T`, `NR_147707.1:n.998C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.411, GERP -1.79 — fast-evolving / accelerated position
- CADD: **PHRED 9.57**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,080 in the highest group · 6/1,613,750 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,360 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,234 |
| European (non-Finnish) | 8.48e-05% | 1,179,876 |

*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}

**CARD8** population constraint: LOEUF 0.883, pLI 1.5184e-08, missense-Z 1.7419. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **262** lies in a UniProt-annotated variant site (in ibd30); the fiind domain; the 'zu5' region.

AlphaFold model confidence (whole protein): pLDDT 71.42, 42% of residues very-high.

**5 experimental structure(s)** (PDB): [4IKM](https://www.rcsb.org/structure/4IKM), [6K9F](https://www.rcsb.org/structure/6K9F), [6XKJ](https://www.rcsb.org/structure/6XKJ), [7JKQ](https://www.rcsb.org/structure/7JKQ), [7JN7](https://www.rcsb.org/structure/7JN7).

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

*Describes the biological roles of CARD8 (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:** CARD8's established molecular role includes NACHT domain binding. p.Asp262= falls in the fiind domain.


### Pathways affected {#pathways}

CARD8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of apoptosome](https://reactome.org/content/detail/R-HSA-111458) | curated |
| [Regulation of the apoptosome activity](https://reactome.org/content/detail/R-HSA-9627069) | curated |

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

**Molecular function:** NACHT domain binding, pattern recognition receptor activity, protein homodimerization activity, CARD domain binding, cysteine-type endopeptidase activator activity, molecular condensate scaffold activity.

**Biological process:** negative regulation of tumor necrosis factor-mediated signaling pathway, protein destabilization, negative regulation of lipopolysaccharide-mediated signaling pathway, negative regulation of interleukin-1 beta production, positive regulation of interleukin-1 beta production, negative regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-18.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-18 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CARD8 variant pages (same residue, condition, or type): [CARD8 c.1035+5G>A](/variant/card8-c-1035-plus-5g-a), [CARD8 p.Ala442Pro](/variant/card8-p-ala442pro), [CARD8 p.Ala97Val](/variant/card8-p-ala97val), [CARD8 p.Arg103His](/variant/card8-p-arg103his), [CARD8 p.Arg20Trp](/variant/card8-p-arg20trp), [CARD8 p.Arg304Gln](/variant/card8-p-arg304gln), [CARD8 p.Arg310Cys](/variant/card8-p-arg310cys), [CARD8 p.Arg353Cys](/variant/card8-p-arg353cys).

### 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 3603715). 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.*