# NM_001242896.3(DEPDC5):c.2190C>T (p.Pro730=)

https://sugi.bio/variant/depdc5-p-pro730

## Summary

**DEPDC5 p.Pro730= (c.2190C>T)** is classified **Likely benign** in DEPDC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-14). Absent from gnomAD v4.1; Associated with familial focal epilepsy with variable foci.

**At a glance:** Likely benign · review: Single submitter · rsID rs762034639 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DEPDC5 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to familial focal epilepsy with variable foci.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Diagnostic panels | DEPDC5 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Familial focal epilepsy with variable foci** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Focal-onset seizure — Very frequent (99-80%)
- EEG with focal epileptiform discharges — Very frequent (99-80%)
- Bilateral tonic-clonic seizure — Frequent (79-30%)
- Interictal EEG abnormality — Frequent (79-30%)
- Nocturnal seizures — Frequent (79-30%)
- Atypical behavior — Occasional (29-5%)
- Autistic behavior — Occasional (29-5%)
- Pallor — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013295/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DEPDC5](https://sugi.bio/atlas/gene/DEPDC5/) |
| Protein change (HGVS p.) | p.Pro730= |
| Coding change (HGVS c.) | c.2190C>T |
| MANE Select transcript | [NM_001242896](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242896) |
| dbSNP | [rs762034639](https://www.ncbi.nlm.nih.gov/snp/rs762034639/) |
| Variant type | single nucleotide variant |
| Location | chr22:31836991-31836991 (GRCh38) |
| ClinVar | [VCV1666682](https://www.ncbi.nlm.nih.gov/clinvar/variation/1666682/) |

**All HGVS expressions:** `NC_000022.10:g.32232977C>T`, `NC_000022.11:g.31836991C>T`, `NG_034067.1:g.88041C>T`, `NM_001136029.4:c.2171-8C>T`, `NM_001242896.3:c.2190C>T`, `NM_001242897.2:c.1956C>T`, `NM_001363852.2:c.2190C>T`, `NM_001363854.2:c.1956C>T`, `NM_001364318.2:c.2190C>T`, `NM_001364319.2:c.1956C>T`, `NM_001364320.2:c.2190C>T`, `NM_001369901.1:c.2106C>T`, `NM_001369902.1:c.2106C>T`, `NM_001369903.1:c.2171-8C>T`, `NM_014662.6:c.2171-8C>T`, `NR_110988.2:n.2162C>T`, `NR_146296.2:n.2279C>T`, `NR_157126.2:n.2279C>T`, `NR_157128.1:n.2396C>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 (below), not from a missing predictor score.
- Conservation: phyloP 4.022, GERP 4.35, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.42**. 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>A, Δ0.20 acceptor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DEPDC5** population constraint: LOEUF 0.403, pLI 1, missense-Z 3.7429; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **focal epilepsy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.22, 19% of residues very-high.

**11 experimental structure(s)** (PDB): [6CES](https://www.rcsb.org/structure/6CES), [6CET](https://www.rcsb.org/structure/6CET), [7T3A](https://www.rcsb.org/structure/7T3A), [7T3B](https://www.rcsb.org/structure/7T3B), [7T3C](https://www.rcsb.org/structure/7T3C), [8FW5](https://www.rcsb.org/structure/8FW5).

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

*Describes the biological roles of DEPDC5 (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:** DEPDC5's established molecular role includes small GTPase binding.


### Pathways affected {#pathways}

DEPDC5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amino acids regulate mTORC1](https://reactome.org/content/detail/R-HSA-9639288) | curated |

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

**Molecular function:** small GTPase binding, protein-containing complex binding.

**Biological process:** cellular response to amino acid starvation, negative regulation of TORC1 signaling.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-14.

**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 | 2024-10-14 |

## Associated conditions {#conditions}

[familial focal epilepsy with variable foci](https://sugi.bio/atlas/disease/familial-focal-epilepsy-with-variable-foci/).

**Reported phenotype names (ClinVar):** Familial focal epilepsy with variable foci.

## Similar variants {#similar}

Related DEPDC5 variant pages (same residue, condition, or type): [DEPDC5 p.Pro730Ser](/variant/depdc5-p-pro730ser), [DEPDC5 p.Pro730His](/variant/depdc5-p-pro730his), [DEPDC5 c.1218-1G>A](/variant/depdc5-c-1218-minus-1g-a), [DEPDC5 c.1287+1G>A](/variant/depdc5-c-1287-plus-1g-a), [DEPDC5 c.1324+1G>A](/variant/depdc5-c-1324-plus-1g-a), [DEPDC5 c.1324+1G>T](/variant/depdc5-c-1324-plus-1g-t), [DEPDC5 c.193+1G>T](/variant/depdc5-c-193-plus-1g-t), [DEPDC5 c.2105-1G>A](/variant/depdc5-c-2105-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1666682). 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.*