Is ALK p.Phe1245Leu (c.3735C>A) pathogenic?

ALK p.Phe1245Leu (c.3735C>A) is classified Pathogenic in ALK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-10-07). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Phe1245Leu (c.3735C>A)?

ALK p.Phe1245Leu (c.3735C>A) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Phe1245Leu (c.3735C>A) in the general population?

ALK p.Phe1245Leu (c.3735C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Phe1245Leu (c.3735C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

ALK p.Phe1245Leu

c.3735C>A · rs863225284 · VCV217857

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 2% in ALK
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -0.044, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 16 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALK
Protein: p.Phe1245Leu
Coding: c.3735C>A
MANE Select: NM_004304
dbSNP: rs863225284
Type: single nucleotide variant
Location: chr2:29213992 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1245: a UniProt-annotated variant site (in nblst3; somatic mutation); the protein kinase domain

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

Disease context

neuroblastoma, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALK p.Phe1245Val Likely pathogenic ★ same residue
ALK p.Phe1245Cys Pathogenic same residue
ALK p.Phe1245Ile Pathogenic same residue
ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>A Uncertain significance ★★ same condition
ALK c.1155-3C>T Uncertain significance ★★ same condition
ALK c.1282+3A>G Uncertain significance ★★ same condition
ALK c.1414+1G>A 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-phe1245leu (accessed [today's date]).

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