Is ALK p.Arg259Cys (c.775C>T) pathogenic?

ALK p.Arg259Cys (c.775C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.6509); Ultra-rare (popmax 0.03%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg259Cys (c.775C>T)?

ALK p.Arg259Cys (c.775C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg259Cys (c.775C>T) in the general population?

ALK p.Arg259Cys (c.775C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about ALK p.Arg259Cys (c.775C>T)?

AlphaMissense predicts likely pathogenic (score 0.6509) — an in-silico prediction, not a clinical call.

ALK p.Arg259Cys

c.775C>T · rs771593278 · VCV404385

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6509 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6509	likely pathogenic
REVEL	0.175	moderately benign-leaning
SaProt	LLR -8.88	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,004 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00211% 34/1,613,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,449
European (non-Finnish)	0.000848%	117,990

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.Arg259Cys
Coding: c.775C>T
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Arg259Gly Uncertain significance ★★ ⚠ same residue
ALK p.Arg259His Benign/Likely benign ★★ same residue
ALK p.Arg259Leu Uncertain significance ★ ⚠ same residue
ALK p.Arg259Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Arg259Ser 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-arg259cys (accessed [today's date]).

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