Is ALK p.Asp418Val (c.1253A>T) pathogenic?

ALK p.Asp418Val (c.1253A>T) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.7728); Very rare (popmax 0.000169%, nfe); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Asp418Val (c.1253A>T)?

ALK p.Asp418Val (c.1253A>T) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Asp418Val (c.1253A>T) in the general population?

ALK p.Asp418Val (c.1253A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ALK p.Asp418Val (c.1253A>T)?

AlphaMissense predicts likely pathogenic (score 0.7728) — an in-silico prediction, not a clinical call.

ALK p.Asp418Val

c.1253A>T · rs2148301472 · VCV3241707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.7728	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -11.51	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	24.5	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,986 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,828 alleles · very rare

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: ALK
Protein: p.Asp418Val
Coding: c.1253A>T
MANE Select: NM_004304
dbSNP: rs2148301472
Type: single nucleotide variant
Location: chr2:29383761 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 418: the mam 1 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.Asp418Gly Uncertain significance ★★ ⚠ same residue
ALK p.Asp418= Likely benign ★★ same residue
ALK p.Asp418Asn Uncertain significance ★ ⚠ same residue
ALK p.Asp418Glu Uncertain significance ★ ⚠ same residue
ALK p.Asp418His Uncertain significance ★ ⚠ 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

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-asp418val (accessed [today's date]).

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