Is ALK p.Phe1323= (c.3969T>C) pathogenic?

ALK p.Phe1323= (c.3969T>C) is classified Likely benign in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-28). Very rare (popmax 0.00133%, afr); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Phe1323= (c.3969T>C)?

ALK p.Phe1323= (c.3969T>C) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Phe1323= (c.3969T>C) in the general population?

ALK p.Phe1323= (c.3969T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

ALK p.Phe1323=

c.3969T>C · rs1372668818 · VCV1105745

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.39	GERP -5.3, phastCons 0.85
Overall
CADD	1.456	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,908 alleles

Overall 6.2e-05% 1/1,613,928 alleles · very rare exomes 0/1,461,774 · genomes 1/152,154 · 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.Phe1323=
Coding: c.3969T>C
MANE Select: NM_004304
dbSNP: rs1372668818
Type: single nucleotide variant
Location: chr2:29197646 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1323: an α-helix; the protein kinase domain

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.Phe1323Leu Uncertain significance ★★ ⚠ same residue
ALK p.Phe1323Cys Uncertain significance ★ ⚠ same residue
ALK p.Phe1323Ser 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

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-phe1323 (accessed [today's date]).

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