Is DLL4 p.Arg191His (c.572G>A) pathogenic?

DLL4 p.Arg191His (c.572G>A) is classified Likely pathogenic in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-02). AlphaMissense: ambiguous (0.3865); Absent from gnomAD v4.1; Associated with DLL4-related disorder.

What condition is associated with DLL4 p.Arg191His (c.572G>A)?

DLL4 p.Arg191His (c.572G>A) is associated with DLL4-related disorder (ClinVar).

How common is DLL4 p.Arg191His (c.572G>A) in the general population?

DLL4 p.Arg191His (c.572G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DLL4 p.Arg191His (c.572G>A)?

AlphaMissense predicts ambiguous (score 0.3865) — an in-silico prediction, not a clinical call.

DLL4 p.Arg191His

c.572G>A · rs1357715175 · VCV2630670

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3865 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

DLL4-related disorder

Computational evidence

Protein change
AlphaMissense	0.3865	ambiguous
REVEL	0.556	indeterminate
SaProt	LLR -12.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,750 bp · p 8.1e-14 · regional, not allelic
Overall
CADD	33.0	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

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.Arg191His
Coding: c.572G>A
MANE Select: NM_019074
dbSNP: rs1357715175
Type: single nucleotide variant
Location: chr15:40931680 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 191: the 'interaction with notch1' region; a disulfide bond; the dsl domain; a β-strand

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

Disease context

DLL4-related disorder

Similar variants

DLL4 p.Gln590Ter Likely pathogenic ★ same condition
DLL4 p.Cys300Tyr Uncertain significance ★ ⚠ same condition
DLL4 p.Tyr666Ter Likely pathogenic same condition
DLL4 c.658+3A>G Uncertain significance same condition
DLL4 p.Pro621Leu Uncertain significance ⚠ same condition
DLL4 p.Glu438= Likely benign same condition
DLL4 p.Leu418= Likely benign same condition
DLL4 p.Cys390Tyr 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/dll4-p-arg191his (accessed [today's date]).

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