Is ALK p.Pro835Leu (c.2504C>T) pathogenic?

ALK p.Pro835Leu (c.2504C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.0659); Ultra-rare (popmax 0.0147%, afr); Associated with ALK-related disorder.

What condition is associated with ALK p.Pro835Leu (c.2504C>T)?

ALK p.Pro835Leu (c.2504C>T) is associated with ALK-related disorder, neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Pro835Leu (c.2504C>T) in the general population?

ALK p.Pro835Leu (c.2504C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about ALK p.Pro835Leu (c.2504C>T)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

ALK p.Pro835Leu

c.2504C>T · rs376091121 · VCV538251

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALK-related disorder

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -7.63	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 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	24.6	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 0.0147% African / African-American · 11/74,944 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00366% 59/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,813
East Asian	0.00668%	14,966
European (non-Finnish)	0.00356%	28,096
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0011%	91,092

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.Pro835Leu
Coding: c.2504C>T
MANE Select: NM_004304
dbSNP: rs376091121
Type: single nucleotide variant
Location: chr2:29232432 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 835: a β-strand

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

Disease context

ALK-related disorder

Also linked: neuroblastoma, susceptibility to, 3 hereditary neoplastic syndrome

Similar variants

ALK p.Pro835= Likely benign ★★ same residue
ALK p.Pro835Ser Conflicting classifications of pathogenicity ★ ⚠ 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
ALK c.1414+3G>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-pro835leu (accessed [today's date]).

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