Is DLL4 p.Arg424His (c.1271G>A) pathogenic?

DLL4 p.Arg424His (c.1271G>A) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0964); Ultra-rare (popmax 0.018%, mid); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Arg424His (c.1271G>A)?

DLL4 p.Arg424His (c.1271G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Arg424His (c.1271G>A) in the general population?

DLL4 p.Arg424His (c.1271G>A) is ultra-rare (popmax 0.018%, mid) (gnomAD).

What do computational predictors say about DLL4 p.Arg424His (c.1271G>A)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

DLL4 p.Arg424His

c.1271G>A · VCV4830448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -4.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	19.29	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 0.018% Middle Eastern · 1/5,554 alleles

Filtering AF 0.00684% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00527%

Overall 0.00224% 36/1,604,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.018%	5,554
South Asian	0.0122%	8,186
Remaining individualsnot grpmax-eligible	0.00644%	15,532
East Asian	0.00448%	22,318
Admixed American	0.00168%	59,526
Finnishnot grpmax-eligible	0.00165%	60,570
European (non-Finnish)	0.00136%	73,545

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.Arg424His
Coding: c.1271G>A
MANE Select: NM_019074
Type: single nucleotide variant
Location: chr15:40936258 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 424: the egf-like 6 domain; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLL4 p.Arg424Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
DLL4 p.Ala450Val Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg313Cys Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg645Gln Uncertain significance ★★ ⚠ same condition
DLL4 p.Glu252Lys Uncertain significance ★★ ⚠ same condition
DLL4 p.His261Arg Uncertain significance ★★ ⚠ same condition
DLL4 p.Leu557Arg Uncertain significance ★★ ⚠ 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/dll4-p-arg424his (accessed [today's date]).

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