Is ALK p.His755= (c.2265C>T) pathogenic?

ALK p.His755= (c.2265C>T) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0267%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.His755= (c.2265C>T)?

ALK p.His755= (c.2265C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.His755= (c.2265C>T) in the general population?

ALK p.His755= (c.2265C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

ALK p.His755=

c.2265C>T · rs770603023 · VCV538306

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

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 -3.9	GERP -4.2
Overall
CADD	5.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/60,002 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0018% 29/1,613,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
African / African-American	0.00534%	18,729
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000593%	168,576

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.His755=
Coding: c.2265C>T
MANE Select: NM_004304
dbSNP: rs770603023
Type: single nucleotide variant
Location: chr2:29239770 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 755: an α-helix

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.His755Arg Uncertain significance ★★ ⚠ same residue
ALK p.His755Gln Uncertain significance ★★ ⚠ same residue
ALK p.His755Leu Uncertain significance ★★ ⚠ same residue
ALK p.His755Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.His755Tyr Uncertain significance ★ ⚠ same residue
ALK p.His755_Ser758del Uncertain significance ★ same residue
ALK p.His755fs Likely benign ★ same residue
ALK p.Arg1275Gln Pathogenic ★★ 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-his755 (accessed [today's date]).

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