Is DLL4 p.Pro131Arg (c.392C>G) pathogenic?

DLL4 p.Pro131Arg (c.392C>G) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely benign (0.1078); Very rare (popmax 8.48e-05%, nfe).

How common is DLL4 p.Pro131Arg (c.392C>G) in the general population?

DLL4 p.Pro131Arg (c.392C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DLL4 p.Pro131Arg (c.392C>G)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

DLL4 p.Pro131Arg

c.392C>G · VCV3640652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -11.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,750 bp · p 8.1e-14 · regional, not allelic
Overall
CADD	22.3	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 8.48e-05% European (non-Finnish) · 1/1,179,812 alleles

Overall 6.84e-05% 1/1,461,316 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.Pro131Arg
Coding: c.392C>G
MANE Select: NM_019074
Type: single nucleotide variant
Location: chr15:40930680 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 131: a turn

Full DLL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLL4 p.Pro131= Uncertain significance ★ 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
DLL4 p.Arg645Gln 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-pro131arg (accessed [today's date]).

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