Is DEPDC5 p.Arg674Cys (c.2020C>T) pathogenic?

DEPDC5 p.Arg674Cys (c.2020C>T) is classified Benign/Likely benign in DEPDC5 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0751); Rare (popmax 0.283%, nfe); Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Arg674Cys (c.2020C>T)?

DEPDC5 p.Arg674Cys (c.2020C>T) is associated with familial focal epilepsy with variable foci, self-limited epilepsy with centrotemporal spikes, epilepsy, familial focal, with variable foci 1 (ClinVar).

How common is DEPDC5 p.Arg674Cys (c.2020C>T) in the general population?

DEPDC5 p.Arg674Cys (c.2020C>T) is rare (popmax 0.283%, 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.Arg674Cys (c.2020C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

DEPDC5 p.Arg674Cys

c.2020C>T · rs181347577 · VCV238673

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.283%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.74 · regional, not allelic
Overall
CADD	25.2	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 0.283% European (non-Finnish) · 3,343/1,179,954 alleles

Filtering AF 0.275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.252% 4,074/1,614,050 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.18%	31
Finnishnot grpmax-eligible	0.694%	144
European (non-Finnish)grpmax	0.283%	353
Remaining individualsnot grpmax-eligible	0.178%	563
South Asian	0.0901%	1,110
African / African-American	0.0546%	1,830
Admixed American	0.0367%	2,728
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,882

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg674Cys
Coding: c.2020C>T
MANE Select: NM_001242896
dbSNP: rs181347577
Type: single nucleotide variant
Location: chr22:31822706 (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

Also linked: self-limited epilepsy with centrotemporal spikes epilepsy, familial focal, with variable foci 1

For Familial focal epilepsy with variable foci (Orphanet):

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

Similar variants

DEPDC5 p.Arg674His 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-arg674cys (accessed [today's date]).

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