Is DLL4 p.Pro370Arg (c.1109C>G) pathogenic?

DLL4 p.Pro370Arg (c.1109C>G) is classified Uncertain significance in DLL4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). AlphaMissense: likely pathogenic (0.8702); Absent from gnomAD v4.1.

How common is DLL4 p.Pro370Arg (c.1109C>G) in the general population?

DLL4 p.Pro370Arg (c.1109C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DLL4 p.Pro370Arg (c.1109C>G)?

AlphaMissense predicts likely pathogenic (score 0.8702) — an in-silico prediction, not a clinical call.

DLL4 p.Pro370Arg

c.1109C>G · rs777481123 · VCV591119

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8702 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8702	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -15.23	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	26.6	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: DLL4
Protein: p.Pro370Arg
Coding: c.1109C>G
MANE Select: NM_019074
dbSNP: rs777481123
Type: single nucleotide variant
Location: chr15:40934986 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 370: the egf-like 5 domain; a disulfide bond

Full DLL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLL4 p.Pro370Leu Uncertain significance ★ ⚠ same residue
DLL4 p.Pro370= Likely benign ★ same residue
DLL4 p.Cys390Tyr Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Cys466Arg Likely pathogenic ★★ same type
DLL4 p.Gln584Ter Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Ala450Val Uncertain significance ★★ ⚠ same type
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same type
DLL4 p.Arg313Cys Uncertain significance ★★ ⚠ 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/dll4-p-pro370arg (accessed [today's date]).

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