Is ALK p.Ser929Phe (c.2786C>T) pathogenic?

ALK p.Ser929Phe (c.2786C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-22). AlphaMissense: likely pathogenic (0.9236); Very rare (popmax 0.0011%, sas); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Ser929Phe (c.2786C>T)?

ALK p.Ser929Phe (c.2786C>T) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Ser929Phe (c.2786C>T) in the general population?

ALK p.Ser929Phe (c.2786C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ALK p.Ser929Phe (c.2786C>T)?

AlphaMissense predicts likely pathogenic (score 0.9236) — an in-silico prediction, not a clinical call.

ALK p.Ser929Phe

c.2786C>T · rs752568687 · VCV640156

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.9236	likely pathogenic
REVEL	0.186	benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	28.9	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 0.0011% South Asian · 1/90,564 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000377% 6/1,589,650 alleles · very rare exomes 6/1,437,868 · genomes 0/151,782 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,564
European (non-Finnish)	0.000432%	231,617

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.Ser929Phe
Coding: c.2786C>T
MANE Select: NM_004304
dbSNP: rs752568687
Type: single nucleotide variant
Location: chr2:29228913 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 929: a β-strand

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.Ser929Ala Uncertain significance ★★ ⚠ same residue
ALK p.Ser929Cys 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
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-ser929phe (accessed [today's date]).

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