Is ALK p.Leu550Phe (c.1648C>T) pathogenic?

ALK p.Leu550Phe (c.1648C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.2924); Rare (popmax 0.107%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Leu550Phe (c.1648C>T)?

ALK p.Leu550Phe (c.1648C>T) is associated with hereditary neoplastic syndrome, ovarian cancer, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Leu550Phe (c.1648C>T) in the general population?

ALK p.Leu550Phe (c.1648C>T) is rare (popmax 0.107%, eas) (gnomAD).

What do computational predictors say about ALK p.Leu550Phe (c.1648C>T)?

AlphaMissense predicts likely benign (score 0.2924) — an in-silico prediction, not a clinical call.

ALK p.Leu550Phe

c.1648C>T · rs769821764 · VCV412915

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2924 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2924	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	28.3	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 0.107% East Asian · 48/44,878 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00316% 51/1,614,180 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,180,011

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.Leu550Phe
Coding: c.1648C>T
MANE Select: NM_004304
dbSNP: rs769821764
Type: single nucleotide variant
Location: chr2:29297057 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 550: 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: ovarian cancer neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Leu550Pro Uncertain significance ★ ⚠ same residue
ALK p.Leu550= Likely benign ★ 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

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-leu550phe (accessed [today's date]).

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