Is HOOK2 p.Gln688Pro (c.2063A>C) pathogenic?

HOOK2 p.Gln688Pro (c.2063A>C) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1294); Ultra-rare (popmax 0.0447%, nfe).

How common is HOOK2 p.Gln688Pro (c.2063A>C) in the general population?

HOOK2 p.Gln688Pro (c.2063A>C) is ultra-rare (popmax 0.0447%, nfe) (gnomAD).

What do computational predictors say about HOOK2 p.Gln688Pro (c.2063A>C)?

AlphaMissense predicts likely benign (score 0.1294) — an in-silico prediction, not a clinical call.

HOOK2 p.Gln688Pro

c.2063A>C · rs200476300 · VCV2525145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1294 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0447%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1294	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -4.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,670 bp · p 0.49 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0447% European (non-Finnish) · 527/1,180,016 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0402%

Overall 0.0344% 555/1,614,144 alleles · ultra-rare exomes 515/1,461,810 · genomes 40/152,334 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0447%	2,239
Admixed American	0.025%	4,002
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.016%	6,250
African / African-American	0.00266%	37,527

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.Gln688Pro
Coding: c.2063A>C
MANE Select: NM_013312
dbSNP: rs200476300
Type: single nucleotide variant
Location: chr19:12763379 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 688: the 'required for localization to the centrosome and induction of aggresome formation' region; the 'sufficient for interaction with cntrl' region

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

Similar variants

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
HK2 p.Ala387Thr 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-gln688pro (accessed [today's date]).

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