# NM_013312.3(HOOK2):c.2074G>T (p.Ala692Ser)

https://sugi.bio/variant/hook2-p-ala692ser

## Summary

**HOOK2 p.Ala692Ser (c.2074G>T)** is classified **Uncertain significance** in HOOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1547); Very rare (popmax 0.00178%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00178%, nfe)

## For patients & families {#patients}

This is a change in the HOOK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HOOK2](https://sugi.bio/atlas/gene/HOOK2/) |
| Protein change (HGVS p.) | p.Ala692Ser |
| Coding change (HGVS c.) | c.2074G>T |
| MANE Select transcript | [NM_013312](https://www.ncbi.nlm.nih.gov/nuccore/NM_013312) |
| Variant type | single nucleotide variant |
| Location | chr19:12763368-12763368 (GRCh38) |
| ClinVar | [VCV4676618](https://www.ncbi.nlm.nih.gov/clinvar/variation/4676618/) |

**All HGVS expressions:** `NC_000019.10:g.12763368C>A`, `NC_000019.9:g.12874182C>A`, `NM_001100176.2:c.2068G>T`, `NM_001400041.1:c.2176G>T`, `NM_001400043.1:c.1849G>T`, `NM_001400044.1:c.1849G>T`, `NM_001400045.1:c.1849G>T`, `NM_001400046.1:c.1849G>T`, `NM_001400047.1:c.1849G>T`, `NM_001400048.1:c.1849G>T`, `NM_013312.3:c.2074G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1547)
- REVEL 0.161 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.486 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.622, GERP 1.4, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 31.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (12,763,285–12,765,955), spanning 2,670 bp. Chi-square p 0.49. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.48**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.48**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00178%** (nfe) · FAF95 0.00114% · FAF99 0.00097% · 21/1,180,046 in the highest group · 22/1,614,052 alleles overall — very rare (popmax 0.00178%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00178% | 56,193 |
| African / African-American | 0.00133% | 74,948 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**HOOK2** population constraint: LOEUF 1.16, pLI 4.6961e-37, missense-Z -0.40144. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **692** lies in the 'required for localization to the centrosome and induction of aggresome formation' region; the 'sufficient for interaction with cntrl' region.

AlphaFold model confidence (whole protein): pLDDT 82.81, 52% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of HOOK2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** HOOK2's established molecular role includes identical protein binding. p.Ala692Ser falls in the required for localization to the centrosome and induction of aggresome formation region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

**Biological process:** endosome organization, lysosome organization, endosome to lysosome transport, early endosome to late endosome transport, protein localization to perinuclear region of cytoplasm.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-13 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related HOOK2 variant pages (same residue, condition, or type): [HK2 p.Asn692=](/variant/hk2-p-asn692), [HK2 p.Arg44Cys](/variant/hk2-p-arg44cys), [HK2 p.Tyr515=](/variant/hk2-p-tyr515), [HOOK2 c.519+7G>T](/variant/hook2-c-519-plus-7g-t), [HOOK2 p.Glu657Lys](/variant/hook2-p-glu657lys), [HOOK2 p.Val445Leu](/variant/hook2-p-val445leu), [HK2 p.Ala352Thr](/variant/hk2-p-ala352thr), [HK2 p.Ala383Thr](/variant/hk2-p-ala383thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4676618). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*