Is ALK p.His1030Pro (c.3089A>C) pathogenic?

ALK p.His1030Pro (c.3089A>C) is classified Conflicting classifications of pathogenicity in ALK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-19). AlphaMissense: likely benign (0.0769); Low-frequency (popmax 1.26%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.His1030Pro (c.3089A>C)?

ALK p.His1030Pro (c.3089A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.His1030Pro (c.3089A>C) in the general population?

ALK p.His1030Pro (c.3089A>C) is low-frequency (popmax 1.26%, mid) (gnomAD).

What do computational predictors say about ALK p.His1030Pro (c.3089A>C)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

ALK p.His1030Pro

c.3089A>C · rs200992945 · VCV1181511

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -4.04	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 0.49	GERP -2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	15.38	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 1.26% Middle Eastern · 59/4,688 alleles

Filtering AF 1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.909%

Overall 0.2% 3,089/1,545,100 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.01%	50
Middle Easterngrpmax	1.26%	79
Admixed American	0.587%	170
East Asian	0.437%	229
Ashkenazi Jewishnot grpmax-eligible	0.247%	404
Remaining individualsnot grpmax-eligible	0.192%	520
South Asian	0.19%	526
African / African-American	0.107%	938
European (non-Finnish)	0.0907%	1,103

Finnish 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.His1030Pro
Coding: c.3089A>C
MANE Select: NM_004304
dbSNP: rs200992945
Type: single nucleotide variant
Location: chr2:29225544 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB

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

Similar variants

ALK p.His1030Gln Uncertain significance ★★ ⚠ same residue
ALK p.His1030Asn Uncertain significance ★ ⚠ same residue
ALK p.His1030= Likely benign ★ same residue
ALK p.His1030del Benign ★ same residue
ALK p.His1030Tyr 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

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-his1030pro (accessed [today's date]).

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