Is DLL4 p.Arg424Ser (c.1270C>A) pathogenic?

DLL4 p.Arg424Ser (c.1270C>A) is classified Conflicting classifications of pathogenicity in DLL4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.3564); Ultra-rare (popmax 0.0135%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Arg424Ser (c.1270C>A)?

DLL4 p.Arg424Ser (c.1270C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Arg424Ser (c.1270C>A) in the general population?

DLL4 p.Arg424Ser (c.1270C>A) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

What do computational predictors say about DLL4 p.Arg424Ser (c.1270C>A)?

AlphaMissense predicts ambiguous (score 0.3564) — an in-silico prediction, not a clinical call.

DLL4 p.Arg424Ser

c.1270C>A · rs373338394 · VCV1411692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3564	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -5.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	21.0	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

Grpmax group 0.0135% European (non-Finnish) · 159/1,176,696 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0114% 183/1,604,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0363%	2,753
European (non-Finnish)grpmax	0.0135%	7,401
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,340
Remaining individualsnot grpmax-eligible	0.00161%	62,130

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg424Ser
Coding: c.1270C>A
MANE Select: NM_019074
dbSNP: rs373338394
Type: single nucleotide variant
Location: chr15:40936257 (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.Arg424His Uncertain significance ★ ⚠ 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-arg424ser (accessed [today's date]).

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