Is ALK p.Ser1448Phe (c.4343C>T) pathogenic?

ALK p.Ser1448Phe (c.4343C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-13). AlphaMissense: likely benign (0.0877); Absent from gnomAD v4.1; Associated with ovarian cancer.

What condition is associated with ALK p.Ser1448Phe (c.4343C>T)?

ALK p.Ser1448Phe (c.4343C>T) is associated with ovarian cancer, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ser1448Phe (c.4343C>T) in the general population?

ALK p.Ser1448Phe (c.4343C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Ser1448Phe (c.4343C>T)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

ALK p.Ser1448Phe

c.4343C>T · rs1553387094 · VCV470871

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -8.78	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 2.8	GERP -2.1, phastCons 0.64
Regional constraint	o/e 1.10	unconstrained · MANE · 4,393 bp · p 0.054 · regional, not allelic
Overall
CADD	16.35	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALK
Protein: p.Ser1448Phe
Coding: c.4343C>T
MANE Select: NM_004304
dbSNP: rs1553387094
Type: single nucleotide variant
Location: chr2:29193744 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1448: the 'disordered' region

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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Ser1448= Conflicting classifications of pathogenicity ★ same residue
ALK p.Ser1448Pro Uncertain significance ★ ⚠ same residue
ALK p.Ser1448fs Uncertain significance ★ same residue
ALK p.Ser1448Thr 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

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-ser1448phe (accessed [today's date]).

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