Is DLL3 p.Arg238Ter (c.712C>T) pathogenic?

DLL3 p.Arg238Ter (c.712C>T) is classified Pathogenic in DLL3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-25). Very rare (popmax 0.005%, amr); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Arg238Ter (c.712C>T)?

DLL3 p.Arg238Ter (c.712C>T) is associated with spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Arg238Ter (c.712C>T) in the general population?

DLL3 p.Arg238Ter (c.712C>T) is very rare (popmax 0.005%, amr) (gnomAD).

DLL3 p.Arg238Ter

c.712C>T · rs104894675 · VCV6833

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

spondylocostal dysostosis 1, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.63, phastCons 0.85
Overall
CADD	38.0	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000868% 14/1,612,900 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
East Asian	0.00446%	22,446
African / African-American	0.00133%	74,928
European (non-Finnish)	0.000678%	147,506

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.Arg238Ter
Coding: c.712C>T
MANE Select: NM_203486
dbSNP: rs104894675
Type: single nucleotide variant
Location: chr19:39504130 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 238: the egf-like 1 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.Arg238Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Cys178Ter Likely pathogenic ★★ same condition
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gly504Asp Pathogenic/Likely pathogenic ★★ same condition
DLL3 c.1758+20C>G Uncertain significance ★★ ⚠ 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-arg238ter (accessed [today's date]).

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