Is DEPDC5 p.Arg1527Pro (c.4580G>C) pathogenic?

DEPDC5 p.Arg1527Pro (c.4580G>C) is classified Uncertain significance in DEPDC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-12). AlphaMissense: likely pathogenic (0.98); Absent from gnomAD v4.1; Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Arg1527Pro (c.4580G>C)?

DEPDC5 p.Arg1527Pro (c.4580G>C) is associated with familial focal epilepsy with variable foci (ClinVar).

How common is DEPDC5 p.Arg1527Pro (c.4580G>C) in the general population?

DEPDC5 p.Arg1527Pro (c.4580G>C) is absent from gnomAD v4.1 (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.Arg1527Pro (c.4580G>C)?

AlphaMissense predicts likely pathogenic (score 0.98) — an in-silico prediction, not a clinical call.

DEPDC5 p.Arg1527Pro

c.4580G>C · VCV3679762

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.98 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.98	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 5.6, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 27 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DEPDC5
Protein: p.Arg1527Pro
Coding: c.4580G>C
MANE Select: NM_001242896
Type: single nucleotide variant
Location: chr22:31906265 (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

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

For Familial focal epilepsy with variable foci (Orphanet):

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

Similar variants

DEPDC5 p.Arg1527Gln Uncertain significance ★★ ⚠ same residue
DEPDC5 p.Arg1527Trp 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-arg1527pro (accessed [today's date]).

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