Is DLL3 p.Met460Leu (c.1378A>C) pathogenic?

DLL3 p.Met460Leu (c.1378A>C) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.2528); Ultra-rare (popmax 0.0285%, nfe).

How common is DLL3 p.Met460Leu (c.1378A>C) in the general population?

DLL3 p.Met460Leu (c.1378A>C) is ultra-rare (popmax 0.0285%, nfe) (gnomAD).

What do computational predictors say about DLL3 p.Met460Leu (c.1378A>C)?

AlphaMissense predicts likely benign (score 0.2528) — an in-silico prediction, not a clinical call.

DLL3 p.Met460Leu

c.1378A>C · rs766274162 · VCV1051911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2528 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2528	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -3.92	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 11	GERP -3.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	22.8	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 0.0285% European (non-Finnish) · 332/1,163,804 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0223% 349/1,566,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0285%	3,505
Remaining individualsnot grpmax-eligible	0.00983%	10,169
African / African-American	0.00946%	10,576
Finnishnot grpmax-eligible	0.00648%	15,439
Admixed American	0.00181%	55,338

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.Met460Leu
Coding: c.1378A>C
MANE Select: NM_203486
dbSNP: rs766274162
Type: single nucleotide variant
Location: chr19:39507323 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 460: the egf-like 6 domain; a disulfide bond

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

Similar variants

DLL3 p.Met460Val Uncertain significance ★★ ⚠ same residue
DLL3 p.Met460Lys Likely pathogenic ★ ⚠ same residue
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

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-met460leu (accessed [today's date]).

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