Is DLL3 p.Pro202fs (c.599_603dup) pathogenic?

DLL3 p.Pro202fs (c.599603dup) is classified Pathogenic in DLL3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-20). Ultra-rare (popmax 0.0175%, afr); Associated with leukodystrophy and acquired microcephaly with or without dystonia;.

How common is DLL3 p.Pro202fs (c.599_603dup) in the general population?

DLL3 p.Pro202fs (c.599_603dup) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

DLL3 p.Pro202fs

Q: What condition is associated with DLL3 p.Pro202fs (c.599_603dup)?

DLL3 p.Pro202fs (c.599_603dup) is associated with leukodystrophy and acquired microcephaly with or without dystonia;, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

c.599_603dup · rs786200899 · VCV6828

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Conditions

leukodystrophy and acquired microcephaly with or without dystonia;

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 1.9	GERP 1.1, phastCons 1
Overall
CADD	32.0	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 0.0175% African / African-American · 12/68,488 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00784%

Overall 0.00828% 123/1,485,052 alleles · ultra-rare exomes 113/1,333,034 · genomes 10/152,018 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,707
Admixed American	0.016%	6,269
Remaining individualsnot grpmax-eligible	0.0104%	9,593
South Asian	0.00891%	11,222
European (non-Finnish)	0.00782%	12,793
Ashkenazi Jewishnot grpmax-eligible	0.00741%	13,503
East Asian	0.00285%	35,080

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.Pro202fs
Coding: c.599_603dup
MANE Select: NM_203486
dbSNP: rs786200899
Type: Microsatellite
Location: chr19:39502998 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 202: the dsl domain

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

Disease context

leukodystrophy and acquired microcephaly with or without dystonia; — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylocostal dysostosis 1, autosomal recessive

Similar variants

DLL3 p.Cys464_Glu465delinsTer Pathogenic ★★ same condition
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Ala317fs Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Arg238Ter Pathogenic ★★ same condition
DLL3 p.Cys178Ter Likely pathogenic ★★ same condition
DLL3 p.Cys207fs Pathogenic ★★ same condition
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys379Tyr 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-pro202fs (accessed [today's date]).

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