Is DLL3 p.Pro361Ser (c.1081C>T) pathogenic?

DLL3 p.Pro361Ser (c.1081C>T) is classified Uncertain significance in DLL3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). AlphaMissense: likely pathogenic (0.5745); Very rare (popmax 0.000339%, nfe).

How common is DLL3 p.Pro361Ser (c.1081C>T) in the general population?

DLL3 p.Pro361Ser (c.1081C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DLL3 p.Pro361Ser (c.1081C>T)?

AlphaMissense predicts likely pathogenic (score 0.5745) — an in-silico prediction, not a clinical call.

DLL3 p.Pro361Ser

c.1081C>T · rs1568450395 · VCV591891

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5745	likely pathogenic
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -14.71	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	29.8	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 0.000339% European (non-Finnish) · 4/1,180,008 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,950 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: DLL3
Protein: p.Pro361Ser
Coding: c.1081C>T
MANE Select: NM_203486
dbSNP: rs1568450395
Type: single nucleotide variant
Location: chr19:39505439 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 361: a disulfide bond; the egf-like 4 domain

Full DLL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLL3 c.652+1G>T Likely pathogenic ★★ same type
DLL3 p.Arg221Ter Pathogenic ★★ same type
DLL3 p.Arg238Ter Pathogenic ★★ same type
DLL3 p.Cys178Ter Likely pathogenic ★★ same type
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Gly504Asp Pathogenic/Likely pathogenic ★★ 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/dll3-p-pro361ser (accessed [today's date]).

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