Is ALK p.Arg259Pro (c.776G>C) pathogenic?

ALK p.Arg259Pro (c.776G>C) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.6438); Very rare (popmax 0.000339%, nfe); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Arg259Pro (c.776G>C)?

ALK p.Arg259Pro (c.776G>C) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Arg259Pro (c.776G>C) in the general population?

ALK p.Arg259Pro (c.776G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ALK p.Arg259Pro (c.776G>C)?

AlphaMissense predicts likely pathogenic (score 0.6438) — an in-silico prediction, not a clinical call.

ALK p.Arg259Pro

c.776G>C · rs138686378 · VCV1024392

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.6438	likely pathogenic
REVEL	0.221	benign-leaning
SaProt	LLR -5.62	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 6	GERP 1.6, 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 0.000339% European (non-Finnish) · 4/1,179,828 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000558% 9/1,613,486 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00626%	15,969
Remaining individualsnot grpmax-eligible	0.0016%	62,446
European (non-Finnish)grpmax	0.000339%	294,957

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg259Pro
Coding: c.776G>C
MANE Select: NM_004304
dbSNP: rs138686378
Type: single nucleotide variant
Location: chr2:29717589 (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

Also linked: hereditary neoplastic syndrome

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.Arg259Leu Uncertain significance ★ ⚠ 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-arg259pro (accessed [today's date]).

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