Is ALK p.Arg259Ser (c.775C>A) pathogenic?

ALK p.Arg259Ser (c.775C>A) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-05). AlphaMissense: likely pathogenic (0.7589); Absent from gnomAD v4.1; Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Arg259Ser (c.775C>A)?

ALK p.Arg259Ser (c.775C>A) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg259Ser (c.775C>A) in the general population?

ALK p.Arg259Ser (c.775C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Arg259Ser (c.775C>A)?

AlphaMissense predicts likely pathogenic (score 0.7589) — an in-silico prediction, not a clinical call.

ALK p.Arg259Ser

c.775C>A · rs771593278 · VCV948994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7589 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,858)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.7589	likely pathogenic
REVEL	0.152	moderately benign-leaning
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	23.2	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

No allele count reported in gnomAD v4.1 (AN 1,613,858). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ALK
Protein: p.Arg259Ser
Coding: c.775C>A
MANE Select: NM_004304
dbSNP: rs771593278
Type: single nucleotide variant
Location: chr2:29717590 (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

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

Similar variants

ALK p.Arg259Gly Uncertain significance ★★ ⚠ same residue
ALK p.Arg259His Benign/Likely benign ★★ same residue
ALK p.Arg259Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Arg259Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Arg259Leu 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-arg259ser (accessed [today's date]).

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