Is ALK p.Pro115Leu (c.344C>T) pathogenic?

ALK p.Pro115Leu (c.344C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-26). AlphaMissense: likely benign (0.0763); Very rare (popmax 0.00234%, sas); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Pro115Leu (c.344C>T)?

ALK p.Pro115Leu (c.344C>T) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Pro115Leu (c.344C>T) in the general population?

ALK p.Pro115Leu (c.344C>T) is very rare (popmax 0.00234%, sas) (gnomAD).

What do computational predictors say about ALK p.Pro115Leu (c.344C>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

ALK p.Pro115Leu

c.344C>T · rs1222939884 · VCV659392

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.8	GERP 0.94, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	11.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00234% South Asian · 2/85,448 alleles

Filtering AF 0.000389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000145%

Overall 0.000578% 9/1,556,988 alleles · very rare exomes 8/1,404,750 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00234%	42,724
Remaining individualsnot grpmax-eligible	0.00166%	60,338
European (non-Finnish)	0.000521%	191,993

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.Pro115Leu
Coding: c.344C>T
MANE Select: NM_004304
dbSNP: rs1222939884
Type: single nucleotide variant
Location: chr2:29920316 (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

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

Also linked: hereditary neoplastic syndrome

Similar variants

ALK p.Pro115Arg Uncertain significance ★★ ⚠ same residue
ALK p.Pro115Ser Uncertain significance ★★ ⚠ same residue
ALK p.Pro115Ala Uncertain significance ★ ⚠ same residue
ALK p.Pro115= 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
ALK c.1282+3A>G 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-pro115leu (accessed [today's date]).

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