Is DEPDC5 p.Ser1073Arg (c.3217A>C) pathogenic?

DEPDC5 p.Ser1073Arg (c.3217A>C) is classified Uncertain significance in DEPDC5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-14). AlphaMissense: ambiguous (0.4567); Very rare (popmax 0.00916%, nfe); Associated with epilepsy, familial focal, with variable foci 1.

What condition is associated with DEPDC5 p.Ser1073Arg (c.3217A>C)?

DEPDC5 p.Ser1073Arg (c.3217A>C) is associated with epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, developmental and epileptic encephalopathy 111 (ClinVar).

How common is DEPDC5 p.Ser1073Arg (c.3217A>C) in the general population?

DEPDC5 p.Ser1073Arg (c.3217A>C) is very rare (popmax 0.00916%, 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.Ser1073Arg (c.3217A>C)?

AlphaMissense predicts ambiguous (score 0.4567) — an in-silico prediction, not a clinical call.

DEPDC5 p.Ser1073Arg

c.3217A>C · rs754608531 · VCV264760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00916%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

epilepsy, familial focal, with variable foci 1

Computational evidence

Protein change
AlphaMissense	0.4567	ambiguous
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 3.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 24 kb · p 0.25 · regional, not allelic
Overall
CADD	21.5	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

Grpmax group 0.00916% European (non-Finnish) · 108/1,179,528 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00707% 114/1,612,624 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00916%	10,922
Remaining individualsnot grpmax-eligible	0.00641%	15,609
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,546
African / African-American	0.00133%	74,920

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.Ser1073Arg
Coding: c.3217A>C
MANE Select: NM_001242896
dbSNP: rs754608531
Type: single nucleotide variant
Location: chr22:31857506 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.22 · 11 PDB
Residue 1073: a UniProt-annotated variant site (in ffevf1; inhibits slightly depdc5 signaling; does not change kinase activity of mtorc1; does not change association with the gator complex; does not change rraga/rragc and rragb/rragc heterodimer formation)

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 developmental and epileptic encephalopathy 111

For Familial focal epilepsy with variable foci (Orphanet):

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

Similar variants

DEPDC5 p.Ser1073Asn 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
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-ser1073arg (accessed [today's date]).

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