Is DLL3 p.Pro206fs (c.602_614dup) pathogenic?

DLL3 p.Pro206fs (c.602614dup) is classified Pathogenic in DLL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). Very rare (popmax 0.00127%, sas); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Pro206fs (c.602_614dup)?

DLL3 p.Pro206fs (c.602_614dup) is associated with spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Pro206fs (c.602_614dup) in the general population?

DLL3 p.Pro206fs (c.602_614dup) is very rare (popmax 0.00127%, sas) (gnomAD).

DLL3 p.Pro206fs

c.602_614dup · rs2079619560 · VCV2736891

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00127%, sas)

Conditions

spondylocostal dysostosis 1, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 1.1, phastCons 1
Overall
CADD	33.0	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 0.00127% South Asian · 1/78,660 alleles

Overall 0.000202% 3/1,486,340 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00174%	57,628
South Asiangrpmax	0.00127%	78,660
European (non-Finnish)	8.88e-05%	1,126,332

Remaining individuals 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: DLL3
Protein: p.Pro206fs
Coding: c.602_614dup
MANE Select: NM_203486
dbSNP: rs2079619560
Type: Duplication
Location: chr19:39503002 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 206: the dsl domain

Full DLL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondylocostal dysostosis 1, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLL3 p.Pro206Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
DLL3 p.Ser416_Cys417insGlyAlaHisArgCysSer Uncertain significance ★★ same condition
DLL3 p.Pro206Ser Benign ★★ same residue
DLL3 p.Asp425fs Likely pathogenic ★ same condition
DLL3 p.Pro437fs Pathogenic ★ same condition
DLL3 p.Pro206= Likely benign ★ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Ala317fs Pathogenic/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/dll3-p-pro206fs (accessed [today's date]).

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