Is ALK p.Leu1190fs (c.3568del) pathogenic?

ALK p.Leu1190fs (c.3568del) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-08). Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Leu1190fs (c.3568del)?

ALK p.Leu1190fs (c.3568del) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

ALK p.Leu1190fs

c.3568del · VCV3717659

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 23 of 29
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: ALK
Protein: p.Leu1190fs
Coding: c.3568del
MANE Select: NM_004304
Type: Deletion
Location: chr2:29220783 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1190: a β-strand; the protein kinase domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Leu1190Pro Uncertain significance ★ ⚠ same residue
ALK p.Leu1190= Likely benign ★ same residue
ALK c.788delG Uncertain significance ★★ same condition
ALK p.Arg918del Uncertain significance ★★ same condition
ALK p.Asn945fs Uncertain significance ★★ same condition
ALK p.Asp602fs Uncertain significance ★★ same condition
ALK p.Cys928_Gly934del Uncertain significance ★★ same condition
ALK p.Glu1409_Lys1410del 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/alk-p-leu1190fs (accessed [today's date]).

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