Is DLL3 p.Cys417Phe (c.1250G>T) pathogenic?

DLL3 p.Cys417Phe (c.1250G>T) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.9444); Absent from gnomAD v4.1.

How common is DLL3 p.Cys417Phe (c.1250G>T) in the general population?

DLL3 p.Cys417Phe (c.1250G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DLL3 p.Cys417Phe (c.1250G>T)?

AlphaMissense predicts likely pathogenic (score 0.9444) — an in-silico prediction, not a clinical call.

DLL3 p.Cys417Phe

c.1250G>T · VCV3710052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9444 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9444	likely pathogenic · top 6% in DLL3
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DLL3
Protein: p.Cys417Phe
Coding: c.1250G>T
MANE Select: NM_203486
Type: single nucleotide variant
Location: chr19:39507195 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 417: the egf-like 5 domain; a disulfide bond

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

Similar variants

DLL3 p.Cys417= Likely benign ★ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same type
DLL3 p.Arg221Ter Pathogenic ★★ same type
DLL3 p.Arg238Ter Pathogenic ★★ same type
DLL3 p.Cys178Ter Likely pathogenic ★★ same type
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same type

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-cys417phe (accessed [today's date]).

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