Is ALK p.Leu9= (c.27C>G) pathogenic?

ALK p.Leu9= (c.27C>G) is classified Benign in ALK (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Leu9= (c.27C>G)?

ALK p.Leu9= (c.27C>G) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

ALK p.Leu9=

Q: How common is ALK p.Leu9= (c.27C>G) in the general population?

ALK p.Leu9= (c.27C>G) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.27C>G · rs4358080 · VCV259269

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 100%, eas) — 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 1.4	GERP -1.8, phastCons 1
Overall
CADD	8.324	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 41,256/41,274 alleles

Filtering AF 99.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.8%

Overall 90.5% 1,396,095/1,541,888 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Admixed American	93.1%	1
European (non-Finnish)	91%	1
Remaining individualsnot grpmax-eligible	90.4%	1
South Asian	88.5%	1
Middle Eastern	86.1%	1
Ashkenazi Jewishnot grpmax-eligible	85.9%	1
Amishnot grpmax-eligible	85.4%	1
Finnishnot grpmax-eligible	85.4%	1
African / African-American	83.5%	1

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.Leu9=
Coding: c.27C>G
MANE Select: NM_004304
dbSNP: rs4358080
Type: single nucleotide variant
Location: chr2:29920633 (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.Leu9Arg Uncertain significance ★★ ⚠ same residue
ALK p.Leu9His Uncertain significance ★ ⚠ same residue
ALK p.Leu9Ile Uncertain significance ★ ⚠ same residue
ALK p.Leu9Phe Uncertain significance ★ ⚠ same residue
ALK p.Leu9_Leu10= Likely benign ★★ same residue
ALK p.Leu9Pro Uncertain significance ★ ⚠ same residue
ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>A 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-leu9 (accessed [today's date]).

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