Is ALK p.Arg412Cys (c.1234C>T) pathogenic?

ALK p.Arg412Cys (c.1234C>T) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.3694); Ultra-rare (popmax 0.0773%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Arg412Cys (c.1234C>T)?

ALK p.Arg412Cys (c.1234C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Arg412Cys (c.1234C>T) in the general population?

ALK p.Arg412Cys (c.1234C>T) is ultra-rare (popmax 0.0773%, afr) (gnomAD).

What do computational predictors say about ALK p.Arg412Cys (c.1234C>T)?

AlphaMissense predicts ambiguous (score 0.3694) — an in-silico prediction, not a clinical call.

ALK p.Arg412Cys

c.1234C>T · rs147102592 · VCV239794

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0773%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3694	ambiguous
REVEL	0.17	moderately benign-leaning
SaProt	LLR -9.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 2.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	27.5	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 0.0773% African / African-American · 58/75,042 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0556%

Overall 0.0268% 432/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.882%	113
Remaining individualsnot grpmax-eligible	0.0832%	1,202
African / African-Americangrpmax	0.0773%	1,294
Middle Eastern	0.0165%	6,060
Admixed American	0.0117%	8,575
European (non-Finnish)	0.00441%	22,692
East Asian	0.00223%	44,872

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg412Cys
Coding: c.1234C>T
MANE Select: NM_004304
dbSNP: rs147102592
Type: single nucleotide variant
Location: chr2:29383780 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 412: the mam 1 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.Arg412Leu Uncertain significance ★★ ⚠ same residue
ALK p.Arg412= Likely benign ★★ same residue
ALK p.Arg412His Conflicting classifications of pathogenicity ★ ⚠ 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-arg412cys (accessed [today's date]).

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