Is DLL3 p.Met460Val (c.1378A>G) pathogenic?

DLL3 p.Met460Val (c.1378A>G) is classified Uncertain significance in DLL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.2296); Ultra-rare (popmax 0.0168%, mid); Associated with syndactyly.

What condition is associated with DLL3 p.Met460Val (c.1378A>G)?

DLL3 p.Met460Val (c.1378A>G) is associated with syndactyly, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Met460Val (c.1378A>G) in the general population?

DLL3 p.Met460Val (c.1378A>G) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about DLL3 p.Met460Val (c.1378A>G)?

AlphaMissense predicts likely benign (score 0.2296) — an in-silico prediction, not a clinical call.

DLL3 p.Met460Val

c.1378A>G · rs766274162 · VCV892590

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2296 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndactyly

Computational evidence

Protein change
AlphaMissense	0.2296	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -4.11	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	22.6	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 0.0168% Middle Eastern · 1/5,950 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.00128% 20/1,566,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,950
African / African-American	0.00675%	14,806
South Asian	0.00115%	86,896
European (non-Finnish)	0.00112%	89,523

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.Met460Val
Coding: c.1378A>G
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

Disease context

syndactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylocostal dysostosis 1, autosomal recessive

Similar variants

DLL3 p.Met460Lys Likely pathogenic ★ ⚠ same residue
DLL3 p.Met460Leu Uncertain significance ★ ⚠ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Arg238Ter Pathogenic ★★ same condition
DLL3 p.Cys178Ter Likely pathogenic ★★ same condition
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ 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-met460val (accessed [today's date]).

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