Is DLL4 p.Arg427His (c.1280G>A) pathogenic?

DLL4 p.Arg427His (c.1280G>A) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.00668%, afr).

How common is DLL4 p.Arg427His (c.1280G>A) in the general population?

DLL4 p.Arg427His (c.1280G>A) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about DLL4 p.Arg427His (c.1280G>A)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

DLL4 p.Arg427His

c.1280G>A · rs771130564 · VCV1400300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00668% African / African-American · 5/74,856 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00137% 22/1,606,790 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,971
South Asian	0.00222%	45,142
Admixed American	0.00168%	59,604
European (non-Finnish)	0.00119%	84,128

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: DLL4
Protein: p.Arg427His
Coding: c.1280G>A
MANE Select: NM_019074
dbSNP: rs771130564
Type: single nucleotide variant
Location: chr15:40936267 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 427: the egf-like 6 domain

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

Similar variants

DLL4 p.Arg427Leu Uncertain significance ★ same residue
DLL4 p.Arg427= 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-arg427his (accessed [today's date]).

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