Is ALK p.Pro157Ser (c.469C>T) pathogenic?

ALK p.Pro157Ser (c.469C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.0658); Ultra-rare (popmax 0.0331%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Pro157Ser (c.469C>T)?

ALK p.Pro157Ser (c.469C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Pro157Ser (c.469C>T) in the general population?

ALK p.Pro157Ser (c.469C>T) is ultra-rare (popmax 0.0331%, nfe) (gnomAD).

What do computational predictors say about ALK p.Pro157Ser (c.469C>T)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

ALK p.Pro157Ser

c.469C>T · rs74774946 · VCV239842

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.22	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 1.2	GERP -3.5, phastCons 0.66
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	11.86	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 0.0331% European (non-Finnish) · 390/1,179,928 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0285% 459/1,612,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.21%	83
Ashkenazi Jewishnot grpmax-eligible	0.0811%	1,233
European (non-Finnish)grpmax	0.0331%	3,025
Remaining individualsnot grpmax-eligible	0.0208%	4,800
Finnishnot grpmax-eligible	0.0175%	5,727
East Asian	0.00892%	11,215
African / African-American	0.00667%	14,990
Admixed American	0.00167%	59,984

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro157Ser
Coding: c.469C>T
MANE Select: NM_004304
dbSNP: rs74774946
Type: single nucleotide variant
Location: chr2:29920191 (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.Pro157Thr Uncertain significance ★★ ⚠ same residue
ALK p.Pro157Arg Uncertain significance ★ ⚠ same residue
ALK p.Pro157Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Pro157= Likely benign ★ same residue
ALK p.Pro157Ala 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

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-pro157ser (accessed [today's date]).

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