Is HOOK2 p.Glu657Lys (c.1969G>A) pathogenic?

HOOK2 p.Glu657Lys (c.1969G>A) is classified Likely benign in HOOK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-08). AlphaMissense: ambiguous (0.341); Low-frequency (popmax 1.08%, nfe).

How common is HOOK2 p.Glu657Lys (c.1969G>A) in the general population?

HOOK2 p.Glu657Lys (c.1969G>A) is low-frequency (popmax 1.08%, nfe) (gnomAD).

What do computational predictors say about HOOK2 p.Glu657Lys (c.1969G>A)?

AlphaMissense predicts ambiguous (score 0.341) — an in-silico prediction, not a clinical call.

HOOK2 p.Glu657Lys

c.1969G>A · rs189241336 · VCV774525

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.341 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.08%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.341	ambiguous
REVEL	0.176	moderately benign-leaning
SaProt	LLR -10.95	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,670 bp · p 0.49 · regional, not allelic
Overall
CADD	25.8	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 1.08% European (non-Finnish) · 12,723/1,180,042 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.868% 14,010/1,614,220 alleles · low-frequency exomes 13,154/1,461,888 · genomes 856/152,332 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.08%	93
Remaining individualsnot grpmax-eligible	0.811%	123
South Asian	0.325%	308
Admixed American	0.277%	362
Finnishnot grpmax-eligible	0.234%	427
Amishnot grpmax-eligible	0.219%	456
Middle Eastern	0.198%	505
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
African / African-American	0.128%	782

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.Glu657Lys
Coding: c.1969G>A
MANE Select: NM_013312
dbSNP: rs189241336
Type: single nucleotide variant
Location: chr19:12763569 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 657: 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

HK2 p.Arg44Cys Uncertain significance ★★ ⚠ same type
HK2 p.Tyr515= Benign ★★ same type
HOOK2 c.519+7G>T 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
HK2 p.Ala464Val 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-glu657lys (accessed [today's date]).

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