Is DLL3 p.Val452= (c.1356C>T) pathogenic?

DLL3 p.Val452= (c.1356C>T) is classified Likely benign in DLL3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Rare (popmax 0.103%, nfe); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Val452= (c.1356C>T)?

DLL3 p.Val452= (c.1356C>T) is associated with spondylocostal dysostosis 1, autosomal recessive, syndactyly (ClinVar).

How common is DLL3 p.Val452= (c.1356C>T) in the general population?

DLL3 p.Val452= (c.1356C>T) is rare (popmax 0.103%, nfe) (gnomAD).

DLL3 p.Val452=

c.1356C>T · rs554268445 · VCV329238

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.103%, nfe)

Conditions

spondylocostal dysostosis 1, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -3.6
Overall
CADD	6.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% European (non-Finnish) · 1,187/1,157,732 alleles

Filtering AF 0.0976% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0957%

Overall 0.0838% 1,302/1,554,352 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.103%	975
Remaining individualsnot grpmax-eligible	0.0808%	1,237
Admixed American	0.0764%	1,309
Middle Eastern	0.0339%	2,951
African / African-American	0.0298%	3,351
Finnishnot grpmax-eligible	0.00222%	45,004

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.Val452=
Coding: c.1356C>T
MANE Select: NM_203486
dbSNP: rs554268445
Type: single nucleotide variant
Location: chr19:39507301 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 452: the egf-like 6 domain; a disulfide bond

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

Also linked: syndactyly

Similar variants

DLL3 p.Val452Ile Likely benign same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Arg238Ter 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

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-val452 (accessed [today's date]).

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