Is DLL4 p.Arg654Pro (c.1961G>C) pathogenic?

DLL4 p.Arg654Pro (c.1961G>C) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.7685); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Arg654Pro (c.1961G>C)?

DLL4 p.Arg654Pro (c.1961G>C) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Arg654Pro (c.1961G>C) in the general population?

DLL4 p.Arg654Pro (c.1961G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about DLL4 p.Arg654Pro (c.1961G>C)?

AlphaMissense predicts likely pathogenic (score 0.7685) — an in-silico prediction, not a clinical call.

DLL4 p.Arg654Pro

c.1961G>C · VCV4839588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7685	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	33.0	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 0.000424% European (non-Finnish) · 5/1,179,316 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,204 alleles · very rare

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.Arg654Pro
Coding: c.1961G>C
MANE Select: NM_019074
Type: single nucleotide variant
Location: chr15:40937435 (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.Arg654Gln Uncertain significance ★ ⚠ same residue
DLL4 p.Arg654Trp 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

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-arg654pro (accessed [today's date]).

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