Is DLL1 p.Arg682fs (c.2044_2045del) pathogenic?

DLL1 p.Arg682fs (c.20442045del) is classified Conflicting classifications of pathogenicity in DLL1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-08-07). Very rare (popmax 0.000254%, nfe); Associated with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures.

How common is DLL1 p.Arg682fs (c.2044_2045del) in the general population?

DLL1 p.Arg682fs (c.2044_2045del) is very rare (popmax 0.000254%, nfe) (gnomAD).

DLL1 p.Arg682fs

Q: What condition is associated with DLL1 p.Arg682fs (c.2044_2045del)?

DLL1 p.Arg682fs (c.2044_2045del) is associated with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (ClinVar).

c.2044_2045del · rs1783602877 · VCV985068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 9 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.35	GERP 0.57, phastCons 0.18
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,860 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,612,670 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00159%	62,934
European (non-Finnish)grpmax	0.000254%	393,287

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: DLL1
Protein: p.Arg682fs
Coding: c.2044_2045del
MANE Select: NM_005618
dbSNP: rs1783602877
Type: Deletion
Location: chr6:170283234 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 682: the 'disordered' region; a UniProt-annotated variant site (in nedbas); a UniProt-annotated variant site (in nedbas; uncertain significance)

Full DLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLL1 p.Glu673fs Pathogenic/Likely pathogenic ★★ same condition
DLL1 p.Gly282fs Pathogenic/Likely pathogenic ★★ same condition
DLL1 c.1250-8_1250-1del Likely pathogenic ★ same condition
DLL1 c.732-2del Likely pathogenic ★ same condition
DLL1 p.Ala418fs Pathogenic ★ same condition
DLL1 p.Arg61fs Pathogenic ★ same condition
DLL1 p.Arg635fs Likely pathogenic ★ same condition
DLL1 p.Cys496fs 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/dll1-p-arg682fs (accessed [today's date]).

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