Is ALK p.Arg133Cys (c.397C>T) pathogenic?

ALK p.Arg133Cys (c.397C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: ambiguous (0.4765); Ultra-rare (popmax 0.019%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg133Cys (c.397C>T)?

ALK p.Arg133Cys (c.397C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg133Cys (c.397C>T) in the general population?

ALK p.Arg133Cys (c.397C>T) is ultra-rare (popmax 0.019%, amr) (gnomAD).

What do computational predictors say about ALK p.Arg133Cys (c.397C>T)?

AlphaMissense predicts ambiguous (score 0.4765) — an in-silico prediction, not a clinical call.

ALK p.Arg133Cys

c.397C>T · rs775940832 · VCV538219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4765 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4765	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -9.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.7, 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 0.019% Admixed American · 11/57,752 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00823%

Overall 0.00106% 17/1,598,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.019%	5,250
European (non-Finnish)	0.000511%	195,572

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.Arg133Cys
Coding: c.397C>T
MANE Select: NM_004304
dbSNP: rs775940832
Type: single nucleotide variant
Location: chr2:29920263 (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.Arg133Leu Uncertain significance ★★ ⚠ same residue
ALK p.Arg133Ser Uncertain significance ★★ ⚠ same residue
ALK p.Arg133His Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Arg133= Likely benign ★ same residue
ALK p.Arg133Gln 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

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-arg133cys (accessed [today's date]).

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