Is DEPDC5 p.Leu558Pro (c.1673T>C) pathogenic?

DEPDC5 p.Leu558Pro (c.1673T>C) is classified Likely pathogenic in DEPDC5 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-18). AlphaMissense: likely benign (0.1676); Absent from gnomAD v4.1; Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Leu558Pro (c.1673T>C)?

DEPDC5 p.Leu558Pro (c.1673T>C) is associated with familial focal epilepsy with variable foci (ClinVar).

How common is DEPDC5 p.Leu558Pro (c.1673T>C) in the general population?

DEPDC5 p.Leu558Pro (c.1673T>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.Leu558Pro (c.1673T>C)?

AlphaMissense predicts likely benign (score 0.1676) — an in-silico prediction, not a clinical call.

DEPDC5 p.Leu558Pro

c.1673T>C · rs2089433234 · VCV934987

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1676 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.1676	likely benign ⚠ discordant with ClinVar
REVEL	0.224	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 4.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 64 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	27.3	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.Leu558Pro
Coding: c.1673T>C
MANE Select: NM_001242896
dbSNP: rs2089433234
Type: single nucleotide variant
Location: chr22:31819028 (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.Leu558= Likely benign ★★ 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
DEPDC5 c.2634-2A>G 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-leu558pro (accessed [today's date]).

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