Is DEPDC5 p.Ser655Phe (c.1964C>T) pathogenic?

DEPDC5 p.Ser655Phe (c.1964C>T) is classified Conflicting classifications of pathogenicity in DEPDC5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-17). AlphaMissense: likely pathogenic (0.7412); Ultra-rare (popmax 0.0601%, eas); Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Ser655Phe (c.1964C>T)?

DEPDC5 p.Ser655Phe (c.1964C>T) is associated with familial focal epilepsy with variable foci, epilepsy, familial focal, with variable foci 1 (ClinVar).

How common is DEPDC5 p.Ser655Phe (c.1964C>T) in the general population?

DEPDC5 p.Ser655Phe (c.1964C>T) is ultra-rare (popmax 0.0601%, eas) (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.Ser655Phe (c.1964C>T)?

AlphaMissense predicts likely pathogenic (score 0.7412) — an in-silico prediction, not a clinical call.

DEPDC5 p.Ser655Phe

c.1964C>T · rs762037579 · VCV1096576

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0601%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.7412	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 4.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.74 · regional, not allelic
Overall
CADD	27.7	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 0.0601% East Asian · 27/44,898 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0364%

Overall 0.00279% 45/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0601%	1,663
Middle Eastern	0.0493%	2,028
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,934
European (non-Finnish)	0.00102%	98,334

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.Ser655Phe
Coding: c.1964C>T
MANE Select: NM_001242896
dbSNP: rs762037579
Type: single nucleotide variant
Location: chr22:31821595 (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: 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.Ser655= Likely benign ★ same residue
DEPDC5 p.Ser655fs Pathogenic ★★ 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-ser655phe (accessed [today's date]).

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