Is DLL4 p.Pro332Leu (c.995C>T) pathogenic?

DLL4 p.Pro332Leu (c.995C>T) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.804); Ultra-rare (popmax 0.0198%, sas); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Pro332Leu (c.995C>T)?

DLL4 p.Pro332Leu (c.995C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Pro332Leu (c.995C>T) in the general population?

DLL4 p.Pro332Leu (c.995C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about DLL4 p.Pro332Leu (c.995C>T)?

AlphaMissense predicts likely pathogenic (score 0.804) — an in-silico prediction, not a clinical call.

DLL4 p.Pro332Leu

c.995C>T · VCV4617426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.804	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0198% South Asian · 18/91,072 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.0013% 19/1,461,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
European (non-Finnish)	8.48e-05%	1,179,834

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.Pro332Leu
Coding: c.995C>T
MANE Select: NM_019074
Type: single nucleotide variant
Location: chr15:40934692 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 332: a disulfide bond; the egf-like 4 domain

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.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
DLL4 p.Met547Thr 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-pro332leu (accessed [today's date]).

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