Is ALK p.His1475fs (c.4421dup) pathogenic?

ALK p.His1475fs (c.4421dup) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.His1475fs (c.4421dup)?

ALK p.His1475fs (c.4421dup) is associated with hereditary neoplastic syndrome (ClinVar).

ALK p.His1475fs

c.4421dup · VCV4271014

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 in the last exon (29 of 29) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.54	GERP -4.9, phastCons 0.004

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

Variant & gene context

Gene: ALK
Protein: p.His1475fs
Coding: c.4421dup
MANE Select: NM_004304
Type: Duplication
Location: chr2:29193665 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB

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.His1475= Benign/Likely benign ★★ same residue
ALK p.His1475Gln Uncertain significance ★ ⚠ same residue
ALK c.3445_3450+13dup Uncertain significance ★★ same condition
ALK p.Ile1105dup Uncertain significance ★★ same condition
ALK p.Lys1525_Glu1526insAspProIleAlaLysLys Uncertain significance ★★ same condition
ALK p.Pro307_Gly308insAla Uncertain significance ★★ same condition
ALK p.Tyr406_Ile407insArgValAlaLeuGluTyr Uncertain significance ★★ same condition
ALK c.2632+11dup Benign/Likely benign ★★ 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-his1475fs (accessed [today's date]).

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