Is DLL4 p.Arg645Trp (c.1933C>T) pathogenic?

DLL4 p.Arg645Trp (c.1933C>T) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1278); Very rare (popmax 0.00519%, amr).

How common is DLL4 p.Arg645Trp (c.1933C>T) in the general population?

DLL4 p.Arg645Trp (c.1933C>T) is very rare (popmax 0.00519%, amr) (gnomAD).

What do computational predictors say about DLL4 p.Arg645Trp (c.1933C>T)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

DLL4 p.Arg645Trp

c.1933C>T · rs376834211 · VCV1495570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00519%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign
REVEL	0.439	indeterminate
SaProt	LLR -7.91	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 1.1	GERP -0.9, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	23.5	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 0.00519% Admixed American · 3/57,854 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000682%

Overall 0.00119% 19/1,599,010 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00519%	19,285
African / African-American	0.00404%	24,751
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,938
Remaining individualsnot grpmax-eligible	0.00324%	30,897
East Asian	0.00224%	44,628
European (non-Finnish)	0.000767%	130,332

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.Arg645Trp
Coding: c.1933C>T
MANE Select: NM_019074
dbSNP: rs376834211
Type: single nucleotide variant
Location: chr15:40936920 (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

Similar variants

DLL4 p.Arg645Gln Uncertain significance ★★ ⚠ same residue
DLL4 p.Arg645= Likely benign ★ same residue
DLL4 p.Cys390Tyr Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Cys466Arg Likely pathogenic ★★ same type
DLL4 p.Gln584Ter Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Ala450Val Uncertain significance ★★ ⚠ same type
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same type
DLL4 p.Arg313Cys Uncertain significance ★★ ⚠ same type

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-arg645trp (accessed [today's date]).

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