Is ALK p.Gln500= (c.1500A>G) pathogenic?

ALK p.Gln500= (c.1500A>G) is classified Benign in ALK (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Common (popmax 92.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Gln500= (c.1500A>G)?

ALK p.Gln500= (c.1500A>G) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

ALK p.Gln500=

Q: How common is ALK p.Gln500= (c.1500A>G) in the general population?

ALK p.Gln500= (c.1500A>G) is common (popmax 92.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1500A>G · rs2293564 · VCV259266

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 92.1%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.012	GERP -2.6, phastCons 0.001
Overall
CADD	7.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 92.1% European (non-Finnish) · 1,086,430/1,179,966 alleles

Filtering AF 91.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 91.9%

Overall 89.4% 1,443,420/1,613,924 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	95.8%	1
European (non-Finnish)grpmax	92.1%	1
Finnishnot grpmax-eligible	91.8%	1
East Asian	90.7%	1
Ashkenazi Jewishnot grpmax-eligible	89.7%	1
Admixed American	88.3%	1
Remaining individualsnot grpmax-eligible	88.2%	1
Middle Eastern	86.9%	1
South Asian	86.6%	1
African / African-American	50.5%	2

Amish 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.Gln500=
Coding: c.1500A>G
MANE Select: NM_004304
dbSNP: rs2293564
Type: single nucleotide variant
Location: chr2:29320797 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 500: the mam 2 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.Gln500His Conflicting classifications of pathogenicity ★ ⚠ 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
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-gln500 (accessed [today's date]).

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