Is DEPDC5 p.Pro44Ala (c.130C>G) pathogenic?

DEPDC5 p.Pro44Ala (c.130C>G) is classified Uncertain significance in DEPDC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-27). AlphaMissense: likely benign (0.2099); Ultra-rare (popmax 0.02%, afr); Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Pro44Ala (c.130C>G)?

DEPDC5 p.Pro44Ala (c.130C>G) is associated with familial focal epilepsy with variable foci (ClinVar).

How common is DEPDC5 p.Pro44Ala (c.130C>G) in the general population?

DEPDC5 p.Pro44Ala (c.130C>G) is ultra-rare (popmax 0.02%, afr) (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.Pro44Ala (c.130C>G)?

AlphaMissense predicts likely benign (score 0.2099) — an in-silico prediction, not a clinical call.

DEPDC5 p.Pro44Ala

c.130C>G · rs756878843 · VCV534808

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.2099	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 3.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 64 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.02% African / African-American · 15/74,854 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0099%

Overall 0.000929% 15/1,613,800 alleles · ultra-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.Pro44Ala
Coding: c.130C>G
MANE Select: NM_001242896
dbSNP: rs756878843
Type: single nucleotide variant
Location: chr22:31758617 (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.Pro44Ser Uncertain significance ★ ⚠ same residue
DEPDC5 p.Pro44= 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

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-pro44ala (accessed [today's date]).

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