Is ALK p.Asp732Asn (c.2194G>A) pathogenic?

ALK p.Asp732Asn (c.2194G>A) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.0853); Very rare (popmax 0.00534%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Asp732Asn (c.2194G>A)?

ALK p.Asp732Asn (c.2194G>A) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3, familial isolated pituitary adenoma (ClinVar).

How common is ALK p.Asp732Asn (c.2194G>A) in the general population?

ALK p.Asp732Asn (c.2194G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ALK p.Asp732Asn (c.2194G>A)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

ALK p.Asp732Asn

c.2194G>A · rs768366852 · VCV576618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.39, phastCons 0.99
Regional constraint	o/e 0.45	unconstrained · MANE · 11 kb · p 0.0014 · regional, not allelic
Overall
CADD	18.84	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00173% 28/1,613,906 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,731
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
East Asian	0.00223%	44,878
European (non-Finnish)	0.00161%	62,105
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,014
South Asian	0.0011%	91,028

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.Asp732Asn
Coding: c.2194G>A
MANE Select: NM_004304
dbSNP: rs768366852
Type: single nucleotide variant
Location: chr2:29251115 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 732: a β-strand

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 familial isolated pituitary adenoma

Similar variants

ALK p.Asp732= Likely benign ★★ same residue
ALK p.Asp732Glu Uncertain significance ★ same residue
ALK p.Asp732Tyr Uncertain significance ★ ⚠ same residue
ALK p.Asp732fs Likely benign ★ 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-asp732asn (accessed [today's date]).

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