Is HOOK2 p.Arg701Pro (c.2102G>C) pathogenic?

HOOK2 p.Arg701Pro (c.2102G>C) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: ambiguous (0.4091); Ultra-rare (popmax 0.0156%, eas).

How common is HOOK2 p.Arg701Pro (c.2102G>C) in the general population?

HOOK2 p.Arg701Pro (c.2102G>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about HOOK2 p.Arg701Pro (c.2102G>C)?

AlphaMissense predicts ambiguous (score 0.4091) — an in-silico prediction, not a clinical call.

HOOK2 p.Arg701Pro

c.2102G>C · rs769580225 · VCV2531976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Computational evidence

Protein change
AlphaMissense	0.4091	ambiguous
REVEL	0.352	indeterminate
SaProt	LLR -7.20	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.27, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,670 bp · p 0.49 · regional, not allelic
Overall
CADD	24.9	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 0.0156% East Asian · 7/44,882 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000558% 9/1,614,126 alleles · ultra-rare exomes 9/1,461,808 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
Remaining individualsnot grpmax-eligible	0.0032%	31,249

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: HOOK2
Protein: p.Arg701Pro
Coding: c.2102G>C
MANE Select: NM_013312
dbSNP: rs769580225
Type: single nucleotide variant
Location: chr19:12763340 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 701: the 'required for localization to the centrosome and induction of aggresome formation' region; the 'sufficient for interaction with cntrl' region; the 'disordered' region

Full HOOK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HOOK2 p.Arg701His Uncertain significance ★ ⚠ same residue
HK2 p.Arg44Cys Uncertain significance ★★ ⚠ same type
HK2 p.Tyr515= Benign ★★ same type
HOOK2 c.519+7G>T Benign ★★ same type
HOOK2 p.Glu657Lys Likely benign ★★ ⚠ same type
HOOK2 p.Val445Leu Benign ★★ same type
HK2 p.Ala352Thr Uncertain significance ★ ⚠ same type
HK2 p.Ala383Thr Uncertain significance ★ ⚠ same type

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/hook2-p-arg701pro (accessed [today's date]).

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