Is HOOK2 p.Thr501Arg (c.1502C>G) pathogenic?

HOOK2 p.Thr501Arg (c.1502C>G) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-30). AlphaMissense: likely benign (0.1789); Ultra-rare (popmax 0.0187%, afr).

How common is HOOK2 p.Thr501Arg (c.1502C>G) in the general population?

HOOK2 p.Thr501Arg (c.1502C>G) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about HOOK2 p.Thr501Arg (c.1502C>G)?

AlphaMissense predicts likely benign (score 0.1789) — an in-silico prediction, not a clinical call.

HOOK2 p.Thr501Arg

c.1502C>G · VCV3858352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1789	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,167 bp · p 0.12 · regional, not allelic
Overall
CADD	23.8	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 0.0187% African / African-American · 14/74,860 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.000936% 15/1,602,128 alleles · ultra-rare exomes 4/1,449,928 · genomes 11/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,347
Admixed American	0.00167%	59,848

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.Thr501Arg
Coding: c.1502C>G
MANE Select: NM_013312
Type: single nucleotide variant
Location: chr19:12766112 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 501: the 'sufficient for interaction with microtubules' 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-thr501arg (accessed [today's date]).

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