Is DLL3 p.Ala456Val (c.1367C>T) pathogenic?

DLL3 p.Ala456Val (c.1367C>T) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.2204); Ultra-rare (popmax 0.0392%, afr); Associated with Inborn genetic diseases.

What condition is associated with DLL3 p.Ala456Val (c.1367C>T)?

DLL3 p.Ala456Val (c.1367C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL3 p.Ala456Val (c.1367C>T) in the general population?

DLL3 p.Ala456Val (c.1367C>T) is ultra-rare (popmax 0.0392%, afr) (gnomAD).

What do computational predictors say about DLL3 p.Ala456Val (c.1367C>T)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

DLL3 p.Ala456Val

c.1367C>T · VCV4617405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -8.01	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 5.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	22.7	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 0.0392% African / African-American · 29/73,966 alleles

Filtering AF 0.028% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0243%

Overall 0.00186% 29/1,560,836 alleles · ultra-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.Ala456Val
Coding: c.1367C>T
MANE Select: NM_203486
Type: single nucleotide variant
Location: chr19:39507312 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 456: the egf-like 6 domain; a disulfide bond

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.Ala456= 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
DLL3 p.Arg160Trp Uncertain significance ★★ ⚠ same condition
DLL3 p.Arg302Cys 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-ala456val (accessed [today's date]).

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