Is DEPDC5 c.1666+252G>A pathogenic?

DEPDC5 c.1666+252G>A is classified Benign in DEPDC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-15). Common (popmax 15.8%, amr) — too common for a highly-penetrant pathogenic allele.

DEPDC5 c.1666+252G>A

Q: How common is DEPDC5 c.1666+252G>A in the general population?

DEPDC5 c.1666+252G>A is common (popmax 15.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs11089530 · VCV1293359

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 15.8%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +252	deep intronic (+252 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -1.4, phastCons 0.001
Overall
CADD	4.991	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.8% Admixed American · 6,437/40,612 alleles

Filtering AF 15.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.4%

Overall 10% 67,779/677,184 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	17.7%	6
Admixed Americangrpmax	15.8%	6
African / African-American	12.9%	8
Finnishnot grpmax-eligible	12.6%	8
Ashkenazi Jewishnot grpmax-eligible	10.9%	9
European (non-Finnish)	10.1%	10
Middle Eastern	9.76%	10
Remaining individualsnot grpmax-eligible	9.72%	10
South Asian	5%	20
East Asian	3.03%	33

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
Coding: c.1666+252G>A
MANE Select: NM_001242896
dbSNP: rs11089530
Type: single nucleotide variant
Location: chr22:31815464 (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

Similar variants

DEPDC5 c.1217+1G>A Likely pathogenic ★★ same type
DEPDC5 c.1218-1G>A Pathogenic ★★ same type
DEPDC5 c.1287+1G>A Pathogenic/Likely pathogenic ★★ same type
DEPDC5 c.1324+1G>A Likely pathogenic ★★ same type
DEPDC5 c.1324+1G>T Likely pathogenic ★★ same type
DEPDC5 c.193+1G>T Pathogenic/Likely pathogenic ★★ same type
DEPDC5 c.2105-1G>A Likely pathogenic ★★ same type
DEPDC5 c.2634-2A>G Likely pathogenic ★★ same type

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-c-1666-plus-252g-a (accessed [today's date]).

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