Is HOOK2 p.Val445Leu (c.1333G>C) pathogenic?

HOOK2 p.Val445Leu (c.1333G>C) is classified Benign in HOOK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-11-10). AlphaMissense: likely benign (0.0827); Low-frequency (popmax 2.73%, eas).

How common is HOOK2 p.Val445Leu (c.1333G>C) in the general population?

HOOK2 p.Val445Leu (c.1333G>C) is low-frequency (popmax 2.73%, eas) (gnomAD).

What do computational predictors say about HOOK2 p.Val445Leu (c.1333G>C)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

HOOK2 p.Val445Leu

c.1333G>C · rs35979347 · VCV784829

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.73%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.72	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 1.7	GERP -2, phastCons 0.95
Regional constraint	o/e 1.08	unconstrained · MANE · 5,167 bp · p 0.12 · regional, not allelic
Overall
CADD	11.3	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 2.73% East Asian · 1,224/44,864 alleles

Filtering AF 2.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.55%

Overall 0.236% 3,809/1,614,010 alleles · low-frequency exomes 3,187/1,461,798 · genomes 622/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	2.73%	37
Admixed American	2.46%	41
Finnishnot grpmax-eligible	1.02%	98
Remaining individualsnot grpmax-eligible	0.275%	363
South Asian	0.0955%	1,047
Middle Eastern	0.0825%	1,212
African / African-American	0.036%	2,778
European (non-Finnish)	0.0142%	7,066
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Val445Leu
Coding: c.1333G>C
MANE Select: NM_013312
dbSNP: rs35979347
Type: single nucleotide variant
Location: chr19:12767435 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81
Residue 445: 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
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-val445leu (accessed [today's date]).

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