Is ALK p.Leu1404Pro (c.4211T>C) pathogenic?

ALK p.Leu1404Pro (c.4211T>C) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0762); Ultra-rare (popmax 0.0493%, mid); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Leu1404Pro (c.4211T>C)?

ALK p.Leu1404Pro (c.4211T>C) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Leu1404Pro (c.4211T>C) in the general population?

ALK p.Leu1404Pro (c.4211T>C) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about ALK p.Leu1404Pro (c.4211T>C)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

ALK p.Leu1404Pro

c.4211T>C · rs377129811 · VCV645717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -5.11	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 3.4	GERP -0.88, phastCons 0.91
Regional constraint	o/e 1.10	unconstrained · MANE · 4,393 bp · p 0.054 · regional, not allelic
Overall
CADD	12.67	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00446% 72/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00186%	53,637
African / African-American	0.00134%	74,890

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.Leu1404Pro
Coding: c.4211T>C
MANE Select: NM_004304
dbSNP: rs377129811
Type: single nucleotide variant
Location: chr2:29193876 (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.Leu1404Phe Uncertain significance ★★ ⚠ same residue
ALK p.Leu1404Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Leu1404= 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
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-leu1404pro (accessed [today's date]).

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