Is ALK p.Val163Leu (c.487G>T) pathogenic?

ALK p.Val163Leu (c.487G>T) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0889); Rare (popmax 0.283%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Val163Leu (c.487G>T)?

ALK p.Val163Leu (c.487G>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Val163Leu (c.487G>T) in the general population?

ALK p.Val163Leu (c.487G>T) is rare (popmax 0.283%, eas) (gnomAD).

What do computational predictors say about ALK p.Val163Leu (c.487G>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

ALK p.Val163Leu

c.487G>T · rs55697431 · VCV133459

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.283%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.60	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 4.8	GERP 0.77, phastCons 0.66
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	15.36	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 0.283% East Asian · 127/44,868 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.228%

Overall 0.0113% 183/1,613,480 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.283%	353
Remaining individualsnot grpmax-eligible	0.0672%	1,488
African / African-American	0.016%	6,257
European (non-Finnish)	0.000169%	590,009

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.Val163Leu
Coding: c.487G>T
MANE Select: NM_004304
dbSNP: rs55697431
Type: single nucleotide variant
Location: chr2:29920173 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 163: a UniProt-annotated variant site (in)

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.Val163Met Conflicting classifications of pathogenicity ★ ⚠ 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
ALK c.1415-3T>C 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-val163leu (accessed [today's date]).

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