Is DLL3 p.Arg356Trp (c.1066C>T) pathogenic?

DLL3 p.Arg356Trp (c.1066C>T) is classified Uncertain significance in DLL3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-08-27). AlphaMissense: ambiguous (0.3979); Rare (popmax 0.131%, mid); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Arg356Trp (c.1066C>T)?

DLL3 p.Arg356Trp (c.1066C>T) is associated with spondylocostal dysostosis 1, autosomal recessive, syndactyly (ClinVar).

How common is DLL3 p.Arg356Trp (c.1066C>T) in the general population?

DLL3 p.Arg356Trp (c.1066C>T) is rare (popmax 0.131%, mid) (gnomAD).

What do computational predictors say about DLL3 p.Arg356Trp (c.1066C>T)?

AlphaMissense predicts ambiguous (score 0.3979) — an in-silico prediction, not a clinical call.

DLL3 p.Arg356Trp

c.1066C>T · rs146274789 · VCV289692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3979 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, mid)

Conditions

spondylocostal dysostosis 1, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.3979	ambiguous
REVEL	0.524	indeterminate
SaProt	LLR -9.22	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -2.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% Middle Eastern · 8/6,084 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.0326% 526/1,613,854 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.131%	761
Remaining individualsnot grpmax-eligible	0.0704%	1,420
Admixed American	0.04%	2,499
Finnishnot grpmax-eligible	0.0375%	2,665
European (non-Finnish)	0.0343%	2,914
South Asian	0.0165%	6,072
African / African-American	0.00668%	14,972
East Asian	0.00223%	44,886

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.Arg356Trp
Coding: c.1066C>T
MANE Select: NM_203486
dbSNP: rs146274789
Type: single nucleotide variant
Location: chr19:39505424 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 356: the egf-like 4 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

Also linked: syndactyly

Similar variants

DLL3 p.Arg356Gln Uncertain significance ★ ⚠ 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-arg356trp (accessed [today's date]).

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