Is ALK p.Ser1448= (c.4344C>T) pathogenic?

ALK p.Ser1448= (c.4344C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-19). Ultra-rare (popmax 0.0166%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ser1448= (c.4344C>T)?

ALK p.Ser1448= (c.4344C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ser1448= (c.4344C>T) in the general population?

ALK p.Ser1448= (c.4344C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

ALK p.Ser1448=

c.4344C>T · rs886055929 · VCV335690

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -3.2, phastCons 0.37
Overall
CADD	1.268	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,020 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000437% 7/1,601,176 alleles · ultra-rare exomes 6/1,448,974 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,020
European (non-Finnish)	0.000512%	195,422

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.Ser1448=
Coding: c.4344C>T
MANE Select: NM_004304
dbSNP: rs886055929
Type: single nucleotide variant
Location: chr2:29193743 (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

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

Also linked: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Ser1448Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Ser1448Pro Uncertain significance ★ ⚠ same residue
ALK p.Ser1448Thr Uncertain significance ★ ⚠ same residue
ALK p.Ser1448fs 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-ser1448 (accessed [today's date]).

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