Is HOOK2 p.Arg175His (c.524G>A) pathogenic?

HOOK2 p.Arg175His (c.524G>A) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely benign (0.1777); Ultra-rare (popmax 0.0267%, afr).

How common is HOOK2 p.Arg175His (c.524G>A) in the general population?

HOOK2 p.Arg175His (c.524G>A) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about HOOK2 p.Arg175His (c.524G>A)?

AlphaMissense predicts likely benign (score 0.1777) — an in-silico prediction, not a clinical call.

HOOK2 p.Arg175His

c.524G>A · rs770714736 · VCV2316437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1777	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -6.28	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 4,213 bp · p 0.38 · regional, not allelic
Overall
CADD	29.8	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 0.0267% African / African-American · 20/74,832 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00174% 28/1,610,852 alleles · ultra-rare exomes 16/1,458,820 · genomes 12/152,032 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,742
Finnishnot grpmax-eligible	0.00157%	63,824
European (non-Finnish)	0.000594%	168,375

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.Arg175His
Coding: c.524G>A
MANE Select: NM_013312
dbSNP: rs770714736
Type: single nucleotide variant
Location: chr19:12771473 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 175: the 'sufficient for interaction with microtubules' region

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

Similar variants

JUNB p.Gly175Ser 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-arg175his (accessed [today's date]).

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