Is ALK p.Glu1381fs (c.4141del) pathogenic?

ALK p.Glu1381fs (c.4141del) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Glu1381fs (c.4141del)?

ALK p.Glu1381fs (c.4141del) is associated with hereditary neoplastic syndrome (ClinVar).

ALK p.Glu1381fs

c.4141del · VCV3285759

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (28 of 29, 23 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1

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

Variant & gene context

Gene: ALK
Protein: p.Glu1381fs
Coding: c.4141del
MANE Select: NM_004304
Type: Deletion
Location: chr2:29196793 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1381: an α-helix; 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

Similar variants

ALK p.Glu1381= Likely benign ★★ same residue
ALK p.Glu1381Val Uncertain significance ★ ⚠ 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-glu1381fs (accessed [today's date]).

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