Is HOOK2 p.Arg695Trp (c.2083C>T) pathogenic?

HOOK2 p.Arg695Trp (c.2083C>T) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely pathogenic (0.6661); Very rare (popmax 0.00439%, sas).

How common is HOOK2 p.Arg695Trp (c.2083C>T) in the general population?

HOOK2 p.Arg695Trp (c.2083C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about HOOK2 p.Arg695Trp (c.2083C>T)?

AlphaMissense predicts likely pathogenic (score 0.6661) — an in-silico prediction, not a clinical call.

HOOK2 p.Arg695Trp

c.2083C>T · rs754554896 · VCV2395893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6661	likely pathogenic · top 9% in HOOK2
REVEL	0.423	indeterminate
SaProt	LLR -11.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.2	GERP 0.28, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,670 bp · p 0.49 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00155% 25/1,614,028 alleles · very rare exomes 22/1,461,812 · genomes 3/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,468
East Asian	0.00223%	44,896
Finnishnot grpmax-eligible	0.00156%	63,992
European (non-Finnish)	0.00127%	78,670

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.Arg695Trp
Coding: c.2083C>T
MANE Select: NM_013312
dbSNP: rs754554896
Type: single nucleotide variant
Location: chr19:12763359 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 695: 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

HOOK2 p.Arg695Gln 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-arg695trp (accessed [today's date]).

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