Is DLL3 p.Ile123fs (c.366_378del) pathogenic?

DLL3 p.Ile123fs (c.366378del) is classified Pathogenic/Likely pathogenic in DLL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-17). Very rare (popmax 0.0011%, sas); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Ile123fs (c.366_378del)?

DLL3 p.Ile123fs (c.366_378del) is associated with spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Ile123fs (c.366_378del) in the general population?

DLL3 p.Ile123fs (c.366_378del) is very rare (popmax 0.0011%, sas) (gnomAD).

DLL3 p.Ile123fs

c.366_378del · rs2079604821 · VCV1324231

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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 3 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Overall 6.84e-05% 1/1,461,066 alleles · very rare

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.Ile123fs
Coding: c.366_378del
MANE Select: NM_203486
dbSNP: rs2079604821
Type: Deletion
Location: chr19:39500629 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42

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.Ile123Val Uncertain significance ★ ⚠ same residue
DLL3 p.Ala317fs Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys207fs Pathogenic ★★ same condition
DLL3 p.Gly132fs Pathogenic ★★ same condition
DLL3 p.Ala81fs Likely pathogenic ★ same condition
DLL3 p.Pro43fs Likely pathogenic ★ same condition
DLL3 p.Pro481fs Likely pathogenic ★ same condition
DLL3 p.Val183fs 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-ile123fs (accessed [today's date]).

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