Is ALK p.Arg1436Cys (c.4306C>T) pathogenic?

ALK p.Arg1436Cys (c.4306C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.00173%, amr); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Arg1436Cys (c.4306C>T)?

ALK p.Arg1436Cys (c.4306C>T) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Arg1436Cys (c.4306C>T) in the general population?

ALK p.Arg1436Cys (c.4306C>T) is very rare (popmax 0.00173%, amr) (gnomAD).

What do computational predictors say about ALK p.Arg1436Cys (c.4306C>T)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

ALK p.Arg1436Cys

c.4306C>T · rs201129468 · VCV1041110

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 2.3, phastCons 0.01

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00173% Admixed American · 1/57,798 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000555% 8/1,441,654 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00173%	57,798
Remaining individualsnot grpmax-eligible	0.00163%	61,524
Finnishnot grpmax-eligible	0.00158%	63,236
European (non-Finnish)	0.000427%	233,932

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.Arg1436Cys
Coding: c.4306C>T
MANE Select: NM_004304
dbSNP: rs201129468
Type: single nucleotide variant
Location: chr2:29193781 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1436: the 'disordered' region

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

Also linked: hereditary neoplastic syndrome

Similar variants

ALK p.Arg1436Ser Uncertain significance ★★ ⚠ same residue
ALK p.Arg1436His Conflicting classifications of pathogenicity ★ ⚠ 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
ALK c.1414+3G>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-arg1436cys (accessed [today's date]).

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