Is ALK p.Ser691= (c.2073C>T) pathogenic?

ALK p.Ser691= (c.2073C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-10). Ultra-rare (popmax 0.0312%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ser691= (c.2073C>T)?

ALK p.Ser691= (c.2073C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ser691= (c.2073C>T) in the general population?

ALK p.Ser691= (c.2073C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

ALK p.Ser691=

c.2073C>T · rs370435082 · VCV470778

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Conditions

hereditary neoplastic syndrome

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 -2.1	GERP -4.7
Overall
CADD	2.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,880 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00229% 37/1,613,678 alleles · ultra-rare exomes 33/1,461,490 · genomes 4/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,206
Middle Eastern	0.0164%	6,082
South Asian	0.00659%	15,172
Admixed American	0.00167%	59,976
African / African-American	0.00133%	74,918
European (non-Finnish)	0.00119%	84,280

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.Ser691=
Coding: c.2073C>T
MANE Select: NM_004304
dbSNP: rs370435082
Type: single nucleotide variant
Location: chr2:29251236 (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.Ser691Arg Uncertain significance ★★ same residue
ALK p.Ser691Asn Uncertain significance ★ ⚠ same residue
ALK p.Ser691Ile 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-ser691 (accessed [today's date]).

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