Is ALK p.Pro367Arg (c.1100C>G) pathogenic?

ALK p.Pro367Arg (c.1100C>G) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.2191); Ultra-rare (popmax 0.0307%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Pro367Arg (c.1100C>G)?

ALK p.Pro367Arg (c.1100C>G) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Pro367Arg (c.1100C>G) in the general population?

ALK p.Pro367Arg (c.1100C>G) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

What do computational predictors say about ALK p.Pro367Arg (c.1100C>G)?

AlphaMissense predicts likely benign (score 0.2191) — an in-silico prediction, not a clinical call.

ALK p.Pro367Arg

c.1100C>G · rs144030155 · VCV133482

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2191	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -9.55	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	21.9	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 0.0307% South Asian · 28/91,078 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0167% 269/1,614,028 alleles · ultra-rare exomes 236/1,461,856 · genomes 33/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,253
European (non-Finnish)	0.0184%	5,438
African / African-American	0.0174%	5,763
Remaining individualsnot grpmax-eligible	0.0144%	6,943
Admixed American	0.00167%	60,012
Finnishnot grpmax-eligible	0.00156%	64,032

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.Pro367Arg
Coding: c.1100C>G
MANE Select: NM_004304
dbSNP: rs144030155
Type: single nucleotide variant
Location: chr2:29531969 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 367: 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.Pro367Ser Uncertain significance ★ ⚠ same residue
ALK p.Pro367Thr 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
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-pro367arg (accessed [today's date]).

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