Is ALK p.Arg259His (c.776G>A) pathogenic?

ALK p.Arg259His (c.776G>A) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.1438); Rare (popmax 0.494%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg259His (c.776G>A)?

ALK p.Arg259His (c.776G>A) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg259His (c.776G>A) in the general population?

ALK p.Arg259His (c.776G>A) is rare (popmax 0.494%, afr) (gnomAD).

What do computational predictors say about ALK p.Arg259His (c.776G>A)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

ALK p.Arg259His

c.776G>A · rs138686378 · VCV133469

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.494%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -6.67	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 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.494% African / African-American · 370/74,938 alleles

Filtering AF 0.452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.436%

Overall 0.0248% 400/1,613,604 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.494%	203
Remaining individualsnot grpmax-eligible	0.0224%	4,462
Admixed American	0.015%	6,667
East Asian	0.00223%	44,864
European (non-Finnish)	0.000509%	196,637

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.Arg259His
Coding: c.776G>A
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

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.Arg259Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg259his (accessed [today's date]).

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