Is ALK c.3359+6C>T pathogenic?

ALK c.3359+6C>T is classified Benign in ALK (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 36.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK c.3359+6C>T?

ALK c.3359+6C>T is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

ALK c.3359+6C>T

Q: How common is ALK c.3359+6C>T in the general population?

ALK c.3359+6C>T is common (popmax 36.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs4622670 · VCV259271

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 36.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +6	donor splice region (+6, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -3.7
Overall
CADD	0.184	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36.1% South Asian · 32,883/91,056 alleles

Filtering AF 35.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.7%

Overall 32.3% 521,065/1,613,208 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	37.8%	3
South Asiangrpmax	36.1%	3
Middle Eastern	35.7%	3
European (non-Finnish)	35.3%	3
Finnishnot grpmax-eligible	34.9%	3
Remaining individualsnot grpmax-eligible	30.8%	3
Amishnot grpmax-eligible	18%	6
Admixed American	17.5%	6
African / African-American	5.83%	17
East Asian	3.37%	30

Ashkenazi Jewish 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
Coding: c.3359+6C>T
MANE Select: NM_004304
dbSNP: rs4622670
Type: single nucleotide variant
Location: chr2:29223336 (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.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
ALK c.1546+4C>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-c-3359-plus-6c-t (accessed [today's date]).

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