Is ALK p.Arg1231Trp (c.3691C>T) pathogenic?

ALK p.Arg1231Trp (c.3691C>T) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2076); Ultra-rare (popmax 0.0567%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg1231Trp (c.3691C>T)?

ALK p.Arg1231Trp (c.3691C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg1231Trp (c.3691C>T) in the general population?

ALK p.Arg1231Trp (c.3691C>T) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about ALK p.Arg1231Trp (c.3691C>T)?

AlphaMissense predicts likely benign (score 0.2076) — an in-silico prediction, not a clinical call.

ALK p.Arg1231Trp

c.3691C>T · rs771475772 · VCV470840

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2076 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2076	likely benign
REVEL	0.562	indeterminate
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 16 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	27.4	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 0.0567% Admixed American · 34/60,012 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00849% 137/1,613,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
European (non-Finnish)	0.00831%	12,041
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Arg1231Trp
Coding: c.3691C>T
MANE Select: NM_004304
dbSNP: rs771475772
Type: single nucleotide variant
Location: chr2:29214036 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1231: an α-helix; the protein kinase domain

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.Arg1231Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Arg1231= 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
ALK c.1414+1G>A Uncertain significance ★★ same condition
ALK c.1414+3G>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-arg1231trp (accessed [today's date]).

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