Is ALK p.Lys1498Arg (c.4493A>G) pathogenic?

ALK p.Lys1498Arg (c.4493A>G) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.111); Very rare (popmax 0.00445%, eas); Associated with ovarian cancer.

What condition is associated with ALK p.Lys1498Arg (c.4493A>G)?

ALK p.Lys1498Arg (c.4493A>G) is associated with ovarian cancer, neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Lys1498Arg (c.4493A>G) in the general population?

ALK p.Lys1498Arg (c.4493A>G) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ALK p.Lys1498Arg (c.4493A>G)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

ALK p.Lys1498Arg

c.4493A>G · rs1475116674 · VCV2445362

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 4,393 bp · p 0.054 · regional, not allelic
Overall
CADD	25.1	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 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000248% 4/1,614,124 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,450
European (non-Finnish)	0.000169%	590,019

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.Lys1498Arg
Coding: c.4493A>G
MANE Select: NM_004304
dbSNP: rs1475116674
Type: single nucleotide variant
Location: chr2:29193594 (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

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3 hereditary neoplastic syndrome

Similar variants

ALK p.Lys1498= Likely benign ★★ same residue
ALK p.Lys1498Glu Uncertain significance ★ ⚠ same residue
ALK p.Lys1498Met 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-lys1498arg (accessed [today's date]).

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