Is ALK p.Arg1275Gln (c.3824G>A) pathogenic?

ALK p.Arg1275Gln (c.3824G>A) is classified Pathogenic in ALK (ClinVar, Multiple submitters, 10 submitters; last evaluated 2024-06-06). AlphaMissense: likely pathogenic (0.9906); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg1275Gln (c.3824G>A)?

ALK p.Arg1275Gln (c.3824G>A) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg1275Gln (c.3824G>A) in the general population?

ALK p.Arg1275Gln (c.3824G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Arg1275Gln (c.3824G>A)?

AlphaMissense predicts likely pathogenic (score 0.9906) — an in-silico prediction, not a clinical call.

ALK p.Arg1275Gln

c.3824G>A · rs113994087 · VCV18083

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9906 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9906	likely pathogenic ✓ concordant with ClinVar · top 9% in ALK
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -14.26	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 16 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	33.0	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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Neuroblastoma	Crizotinib	C	Sensitivity/Response
Neuroblastoma	Crizotinib	C	Sensitivity/Response
Neuroblastoma	Lorlatinib	D	Sensitivity/Response
Neuroblastoma	Crizotinib	D	Sensitivity/Response
Neuroblastoma	Crizotinib	B	Sensitivity/Response
Neuroblastoma	ALK Inhibitor TAE684	D	Sensitivity/Response
Neuroblastoma	ALK Inhibitor TAE684	D	Resistance
Neuroblastoma		B	Predisposition

Variant & gene context

Gene: ALK
Protein: p.Arg1275Gln
Coding: c.3824G>A
MANE Select: NM_004304
dbSNP: rs113994087
Type: single nucleotide variant
Location: chr2:29209798 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1275: an α-helix; a UniProt-annotated variant site (observed in neuroblastoma); a UniProt-annotated variant site (in nblst3; constitutively activated; retained in the endoplasmic reticulum and golgi compartments); 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

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Arg1275Ter Uncertain significance ★★ same residue
ALK p.Arg1275= Likely benign ★ same residue
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
ALK c.1415-3T>C 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-arg1275gln (accessed [today's date]).

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