Is DEPDC5 p.Ala641Val (c.1922C>T) pathogenic?

DEPDC5 p.Ala641Val (c.1922C>T) is classified Benign in DEPDC5 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1109); Common (popmax 5.65%, sas) — too common for a highly-penetrant pathogenic allele; Associated with familial focal epilepsy with variable foci.

What condition is associated with DEPDC5 p.Ala641Val (c.1922C>T)?

DEPDC5 p.Ala641Val (c.1922C>T) is associated with familial focal epilepsy with variable foci (ClinVar).

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.Ala641Val (c.1922C>T)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

DEPDC5 p.Ala641Val

Q: How common is DEPDC5 p.Ala641Val (c.1922C>T) in the general population?

DEPDC5 p.Ala641Val (c.1922C>T) is common (popmax 5.65%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1922C>T · rs16989528 · VCV257659

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.65%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial focal epilepsy with variable foci

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.90	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 0.27	GERP 1.4, phastCons 0.021
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.74 · regional, not allelic
Overall
CADD	19.29	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 5.65% South Asian · 5,149/91,076 alleles

Filtering AF 5.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.47%

Overall 3.39% 54,688/1,614,110 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	7.76%	13
South Asiangrpmax	5.65%	18
Remaining individualsnot grpmax-eligible	3.35%	30
European (non-Finnish)	3.3%	30
Middle Eastern	3.28%	30
East Asian	2.59%	39
Ashkenazi Jewishnot grpmax-eligible	2.49%	40
Admixed American	1.71%	58
African / African-American	0.51%	196
Amishnot grpmax-eligible	0.219%	456

Finnish 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.Ala641Val
Coding: c.1922C>T
MANE Select: NM_001242896
dbSNP: rs16989528
Type: single nucleotide variant
Location: chr22:31821553 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.22 · 11 PDB
Residue 641: a UniProt-annotated variant site (in)

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.Ala641Thr Uncertain significance ★ ⚠ same residue
DEPDC5 p.Ala641= 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-ala641val (accessed [today's date]).

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