Is DEPDC5 p.Leu277Phe (c.829C>T) pathogenic?

DEPDC5 p.Leu277Phe (c.829C>T) is classified Uncertain significance in DEPDC5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.7215); Ultra-rare (popmax 0.0263%, sas); Associated with Inborn genetic diseases.

What condition is associated with DEPDC5 p.Leu277Phe (c.829C>T)?

DEPDC5 p.Leu277Phe (c.829C>T) is associated with Inborn genetic diseases, familial focal epilepsy with variable foci, epilepsy, familial focal, with variable foci 1 (ClinVar).

How common is DEPDC5 p.Leu277Phe (c.829C>T) in the general population?

DEPDC5 p.Leu277Phe (c.829C>T) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about DEPDC5 p.Leu277Phe (c.829C>T)?

AlphaMissense predicts likely pathogenic (score 0.7215) — an in-silico prediction, not a clinical call.

DEPDC5 p.Leu277Phe

c.829C>T · rs778656662 · VCV1007024

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7215 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7215	likely pathogenic
REVEL	0.211	benign-leaning
SaProt	LLR -6.34	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 7.7	GERP 3.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 64 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	26.6	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 0.0263% South Asian · 24/91,088 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00173% 28/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,795
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,888

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.Leu277Phe
Coding: c.829C>T
MANE Select: NM_001242896
dbSNP: rs778656662
Type: single nucleotide variant
Location: chr22:31797661 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.22 · 11 PDB
Residue 277: an α-helix

Full DEPDC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial focal epilepsy with variable foci epilepsy, familial focal, with variable foci 1

Similar variants

DEPDC5 p.Leu277Ile Uncertain significance ★★ ⚠ same residue
DEPDC5 c.1217+1G>A Likely pathogenic ★★ same condition
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-leu277phe (accessed [today's date]).

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