Is ALK p.Phe168Ser (c.503T>C) pathogenic?

ALK p.Phe168Ser (c.503T>C) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9771); Ultra-rare (popmax 0.0119%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Phe168Ser (c.503T>C)?

ALK p.Phe168Ser (c.503T>C) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Phe168Ser (c.503T>C) in the general population?

ALK p.Phe168Ser (c.503T>C) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

What do computational predictors say about ALK p.Phe168Ser (c.503T>C)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

ALK p.Phe168Ser

c.503T>C · rs755498584 · VCV404315

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -11.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0119% European (non-Finnish) · 141/1,180,026 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00972%

Overall 0.0088% 142/1,613,604 alleles · ultra-rare exomes 137/1,461,386 · genomes 5/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,369
Admixed American	0.00167%	60,008

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.Phe168Ser
Coding: c.503T>C
MANE Select: NM_004304
dbSNP: rs755498584
Type: single nucleotide variant
Location: chr2:29920157 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Phe168= Likely benign ★★ same residue
ALK p.Phe168Leu 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-phe168ser (accessed [today's date]).

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