Is ALK p.Pro542Arg (c.1625C>G) pathogenic?

ALK p.Pro542Arg (c.1625C>G) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: likely pathogenic (0.7056); Ultra-rare (popmax 0.0165%, mid); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Pro542Arg (c.1625C>G)?

ALK p.Pro542Arg (c.1625C>G) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Pro542Arg (c.1625C>G) in the general population?

ALK p.Pro542Arg (c.1625C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ALK p.Pro542Arg (c.1625C>G)?

AlphaMissense predicts likely pathogenic (score 0.7056) — an in-silico prediction, not a clinical call.

ALK p.Pro542Arg

c.1625C>G · rs372456536 · VCV2151222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7056 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.7056	likely pathogenic
REVEL	0.342	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	24.2	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000124% 2/1,613,594 alleles · ultra-rare exomes 2/1,461,302 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	8.48e-05%	1,179,522

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.Pro542Arg
Coding: c.1625C>G
MANE Select: NM_004304
dbSNP: rs372456536
Type: single nucleotide variant
Location: chr2:29318326 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 542: the mam 2 domain

Full ALK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuroblastoma, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALK p.Pro542Leu Uncertain significance ★★ ⚠ same residue
ALK p.Pro542= Benign/Likely benign ★★ same residue
ALK p.Pro542Ser 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-pro542arg (accessed [today's date]).

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