Is ALK p.Ala909= (c.2727C>T) pathogenic?

ALK p.Ala909= (c.2727C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-29). Very rare (popmax 0.00108%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ala909= (c.2727C>T)?

ALK p.Ala909= (c.2727C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ala909= (c.2727C>T) in the general population?

ALK p.Ala909= (c.2727C>T) is very rare (popmax 0.00108%, nfe) (gnomAD).

ALK p.Ala909=

c.2727C>T · rs1236590521 · VCV1099383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00108%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 0.058, phastCons 1
Overall
CADD	12.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00108% European (non-Finnish) · 12/1,109,472 alleles

Filtering AF 0.000577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000456%

Overall 0.000798% 12/1,502,924 alleles · very rare

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.Ala909=
Coding: c.2727C>T
MANE Select: NM_004304
dbSNP: rs1236590521
Type: single nucleotide variant
Location: chr2:29228972 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 909: an α-helix; a disulfide bond

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.Ala909Thr Uncertain significance ★★ ⚠ same residue
ALK p.Ala909Asp Uncertain significance ★ ⚠ same residue
ALK p.Ala909Val 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
ALK c.1282+3A>G Uncertain significance ★★ same condition
ALK c.1414+1G>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-ala909 (accessed [today's date]).

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