Is HOOK2 p.Glu126Lys (c.376G>A) pathogenic?

HOOK2 p.Glu126Lys (c.376G>A) is classified Uncertain significance in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.143); Very rare (popmax 0.00801%, afr).

How common is HOOK2 p.Glu126Lys (c.376G>A) in the general population?

HOOK2 p.Glu126Lys (c.376G>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about HOOK2 p.Glu126Lys (c.376G>A)?

AlphaMissense predicts likely benign (score 0.143) — an in-silico prediction, not a clinical call.

HOOK2 p.Glu126Lys

c.376G>A · rs751363422 · VCV2588967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.143	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -12.63	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 4,213 bp · p 0.38 · regional, not allelic
Overall
CADD	27.6	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 0.00801% African / African-American · 6/74,950 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00118% 19/1,614,002 alleles · very rare exomes 15/1,461,762 · genomes 4/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,492
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000932%	107,273

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.Glu126Lys
Coding: c.376G>A
MANE Select: NM_013312
dbSNP: rs751363422
Type: single nucleotide variant
Location: chr19:12772792 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 126: the 'sufficient for interaction with microtubules' region; the 'required for localization to the centrosome and induction of aggresome formation' 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-glu126lys (accessed [today's date]).

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