Is DLL4 p.Arg23His (c.68G>A) pathogenic?

DLL4 p.Arg23His (c.68G>A) is classified Likely benign in DLL4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1293); Rare (popmax 0.127%, amr); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Arg23His (c.68G>A)?

DLL4 p.Arg23His (c.68G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Arg23His (c.68G>A) in the general population?

DLL4 p.Arg23His (c.68G>A) is rare (popmax 0.127%, amr) (gnomAD).

What do computational predictors say about DLL4 p.Arg23His (c.68G>A)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

DLL4 p.Arg23His

c.68G>A · rs370744960 · VCV1583316

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -8.20	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 2.3	GERP -2.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,750 bp · p 8.1e-14 · regional, not allelic
Overall
CADD	19.53	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

Grpmax group 0.127% Admixed American · 76/59,966 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0954%

Overall 0.00875% 141/1,610,786 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.127%	789
European (non-Finnish)	0.00526%	19,023
Remaining individualsnot grpmax-eligible	0.0032%	31,213
East Asian	0.00223%	44,866

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.Arg23His
Coding: c.68G>A
MANE Select: NM_019074
dbSNP: rs370744960
Type: single nucleotide variant
Location: chr15:40929848 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB

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.Arg23= Likely benign ★ 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-arg23his (accessed [today's date]).

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