Is ALK p.Ser226Phe (c.677C>T) pathogenic?

ALK p.Ser226Phe (c.677C>T) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-26). AlphaMissense: likely benign (0.0818); Very rare (popmax 0.000169%, nfe); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Ser226Phe (c.677C>T)?

ALK p.Ser226Phe (c.677C>T) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ser226Phe (c.677C>T) in the general population?

ALK p.Ser226Phe (c.677C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ALK p.Ser226Phe (c.677C>T)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

ALK p.Ser226Phe

c.677C>T · rs1679303562 · VCV965852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -8.34	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 3.9	GERP -2.2, phastCons 0.94
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	3.853	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 0.000169% European (non-Finnish) · 2/1,180,012 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,138 alleles · very rare exomes 2/1,461,840 · genomes 0/152,298 · joint denominator

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.Ser226Phe
Coding: c.677C>T
MANE Select: NM_004304
dbSNP: rs1679303562
Type: single nucleotide variant
Location: chr2:29717688 (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

Similar variants

ALK p.Ser226= 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
ALK c.1414+3G>A Uncertain significance ★★ same condition
ALK c.1415-3T>C 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-ser226phe (accessed [today's date]).

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