Is DLL3 p.Pro481Arg (c.1442C>G) pathogenic?

DLL3 p.Pro481Arg (c.1442C>G) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely benign (0.0614); Ultra-rare (popmax 0.0175%, mid); Associated with Inborn genetic diseases.

What condition is associated with DLL3 p.Pro481Arg (c.1442C>G)?

DLL3 p.Pro481Arg (c.1442C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DLL3 p.Pro481Arg (c.1442C>G) in the general population?

DLL3 p.Pro481Arg (c.1442C>G) is ultra-rare (popmax 0.0175%, mid) (gnomAD).

What do computational predictors say about DLL3 p.Pro481Arg (c.1442C>G)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

DLL3 p.Pro481Arg

c.1442C>G · rs2514649503 · VCV2281659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.049	GERP -2.9
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	8.125	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 0.0175% Middle Eastern · 1/5,704 alleles

Overall 0.00014% 2/1,424,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0175%	5,704
Remaining individualsnot grpmax-eligible	0.00164%	61,160

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: DLL3
Protein: p.Pro481Arg
Coding: c.1442C>G
MANE Select: NM_203486
dbSNP: rs2514649503
Type: single nucleotide variant
Location: chr19:39507387 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42

Full DLL3 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

DLL3 p.Pro481Ala Uncertain significance ★★ ⚠ same residue
DLL3 p.Pro481Leu Uncertain significance ★ ⚠ same residue
DLL3 p.Pro481= Likely benign ★ same residue
DLL3 c.1758+20C>G Uncertain significance ★★ ⚠ same condition
DLL3 p.Ala139Thr Uncertain significance ★★ ⚠ same condition
DLL3 p.Ala446Val Uncertain significance ★★ ⚠ same condition
DLL3 p.Ala96Glu Uncertain significance ★★ ⚠ same condition
DLL3 p.Ala96Thr 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/dll3-p-pro481arg (accessed [today's date]).

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