Is ALK p.Ser716= (c.2148C>T) pathogenic?

ALK p.Ser716= (c.2148C>T) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Rare (popmax 0.742%, eas); Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Ser716= (c.2148C>T)?

ALK p.Ser716= (c.2148C>T) is associated with neuroblastoma, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Ser716= (c.2148C>T) in the general population?

ALK p.Ser716= (c.2148C>T) is rare (popmax 0.742%, eas) (gnomAD).

ALK p.Ser716=

c.2148C>T · rs55733526 · VCV239801

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.742%, eas)

Conditions

neuroblastoma, susceptibility to, 3

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 -0.23	GERP -3, phastCons 0.002
Overall
CADD	7.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.742% East Asian · 333/44,868 alleles

Filtering AF 0.677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.651%

Overall 0.0309% 499/1,614,036 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.742%	135
Remaining individualsnot grpmax-eligible	0.216%	463
African / African-American	0.016%	6,252
Admixed American	0.00667%	15,003
South Asian	0.0022%	45,524
European (non-Finnish)	0.0011%	90,768

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.Ser716=
Coding: c.2148C>T
MANE Select: NM_004304
dbSNP: rs55733526
Type: single nucleotide variant
Location: chr2:29251161 (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

Also linked: hereditary neoplastic syndrome

Similar variants

ALK p.Ser716Ile Uncertain significance ★★ ⚠ same residue
ALK p.Ser716Arg Uncertain significance ★ ⚠ same residue
ALK p.Ser716Asn Uncertain significance ★ ⚠ same residue
ALK p.Ser716Gly Uncertain significance ★ ⚠ same residue
ALK p.Ser716Thr 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

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-ser716 (accessed [today's date]).

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