Is HOOK2 p.His488Gln (c.1464C>G) pathogenic?

HOOK2 p.His488Gln (c.1464C>G) is classified Conflicting classifications of pathogenicity in HOOK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2020-10-29). AlphaMissense: likely benign (0.1098); Common (popmax 40.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with scoliosis, isolated, susceptibility to, 1.

What condition is associated with HOOK2 p.His488Gln (c.1464C>G)?

HOOK2 p.His488Gln (c.1464C>G) is associated with scoliosis, isolated, susceptibility to, 1 (ClinVar).

What do computational predictors say about HOOK2 p.His488Gln (c.1464C>G)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

HOOK2 p.His488Gln

Q: How common is HOOK2 p.His488Gln (c.1464C>G) in the general population?

HOOK2 p.His488Gln (c.1464C>G) is common (popmax 40.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1464C>G · rs897804 · VCV1225367

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40.9%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

scoliosis, isolated, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -3.83	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 3.9	GERP -0.001, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,167 bp · p 0.12 · regional, not allelic
Overall
CADD	20.1	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 40.9% Middle Eastern · 2,349/5,740 alleles

Filtering AF 40.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 40%

Overall 36.3% 580,517/1,599,928 alleles · common exomes 536,196/1,447,762 · genomes 44,321/152,166 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	46.3%	2
Middle Easterngrpmax	40.9%	2
European (non-Finnish)	40.2%	2
Finnishnot grpmax-eligible	37.1%	3
Amishnot grpmax-eligible	37.1%	3
Remaining individualsnot grpmax-eligible	35%	3
Admixed American	25.8%	4
East Asian	23.2%	4
South Asian	20.2%	5
African / African-American	7.19%	14

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His488Gln
Coding: c.1464C>G
MANE Select: NM_013312
dbSNP: rs897804
Type: single nucleotide variant
Location: chr19:12766150 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 488: a UniProt-annotated variant site (in); the 'sufficient for interaction with microtubules' region

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

Disease context

scoliosis, isolated, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-his488gln (accessed [today's date]).

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