Is DEPDC5 p.Asp1359Val (c.4076A>T) pathogenic?

DEPDC5 p.Asp1359Val (c.4076A>T) is classified Uncertain significance in DEPDC5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-11). AlphaMissense: likely pathogenic (0.9148); Very rare (popmax 8.48e-05%, nfe); Associated with epilepsy, familial focal, with variable foci 1.

What condition is associated with DEPDC5 p.Asp1359Val (c.4076A>T)?

DEPDC5 p.Asp1359Val (c.4076A>T) is associated with epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci (ClinVar).

How common is DEPDC5 p.Asp1359Val (c.4076A>T) in the general population?

DEPDC5 p.Asp1359Val (c.4076A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Familial focal epilepsy with variable foci inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DEPDC5 p.Asp1359Val (c.4076A>T)?

AlphaMissense predicts likely pathogenic (score 0.9148) — an in-silico prediction, not a clinical call.

DEPDC5 p.Asp1359Val

c.4076A>T · rs769196883 · VCV1737583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, familial focal, with variable foci 1

Computational evidence

Protein change
AlphaMissense	0.9148	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -10.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 3.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 27 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,684 alleles

Overall 6.84e-05% 1/1,460,992 alleles · very rare

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: DEPDC5
Protein: p.Asp1359Val
Coding: c.4076A>T
MANE Select: NM_001242896
dbSNP: rs769196883
Type: single nucleotide variant
Location: chr22:31893624 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.22 · 11 PDB

Full DEPDC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, familial focal, with variable foci 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial focal epilepsy with variable foci

For Familial focal epilepsy with variable foci (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

DEPDC5 p.Asp1359= Likely benign ★ same residue
DEPDC5 p.Asp1359His Uncertain significance ★ ⚠ same residue
DEPDC5 c.1218-1G>A Pathogenic ★★ same condition
DEPDC5 c.1287+1G>A Pathogenic/Likely pathogenic ★★ same condition
DEPDC5 c.1324+1G>A Likely pathogenic ★★ same condition
DEPDC5 c.1324+1G>T Likely pathogenic ★★ same condition
DEPDC5 c.193+1G>T Pathogenic/Likely pathogenic ★★ same condition
DEPDC5 c.2105-1G>A Likely 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/depdc5-p-asp1359val (accessed [today's date]).

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