# NM_004850.5(ROCK2):c.1802A>T (p.Asp601Val)

https://sugi.bio/variant/rock2-p-asp601val

## Summary

**ROCK2 p.Asp601Val (c.1802A>T)** is classified **Conflicting classifications of pathogenicity** in ROCK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2558); Ultra-rare (popmax 0.0693%, nfe); Associated with volvulus of midgut.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs35768389 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0693%, nfe)

## For patients & families {#patients}

This is a change in the ROCK2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to volvulus of midgut.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027787/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ROCK2](https://sugi.bio/atlas/gene/ROCK2/) |
| Protein change (HGVS p.) | p.Asp601Val |
| Coding change (HGVS c.) | c.1802A>T |
| MANE Select transcript | [NM_004850](https://www.ncbi.nlm.nih.gov/nuccore/NM_004850) |
| dbSNP | [rs35768389](https://www.ncbi.nlm.nih.gov/snp/rs35768389/) |
| Variant type | single nucleotide variant |
| Location | chr2:11214974-11214974 (GRCh38) |
| ClinVar | [VCV1686313](https://www.ncbi.nlm.nih.gov/clinvar/variation/1686313/) |

**All HGVS expressions:** `NC_000002.11:g.11355100T>A`, `NC_000002.12:g.11214974T>A`, `NG_029769.1:g.134612A>T`, `NM_001321643.2:c.1544A>T`, `NM_004850.5:c.1802A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2558)
- REVEL 0.251 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.882 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.922, GERP 1.96, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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 0.81** across the covering region of the MANE Select transcript (11,198,538–11,221,211), spanning 22,673 bp. Chi-square p 5.3e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0693%** (nfe) · FAF95 0.0653% · FAF99 0.0638% · 818/1,180,010 in the highest group · 853/1,613,998 alleles overall — ultra-rare (popmax 0.0693%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0693% | 1,443 |
| Remaining individuals (not grpmax-eligible) | 0.0384% | 2,604 |
| African / African-American | 0.00934% | 10,702 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,339 |
| Admixed American | 0.00167% | 60,006 |

*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}

**ROCK2** population constraint: LOEUF 0.346, pLI 1, missense-Z 4.2964. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital heart disease** — Limited (AD)

## Protein context {#protein}

Residue **601** lies in a UniProt-annotated variant site (in); the 'interaction with ppp1r12a' region.

AlphaFold model confidence (whole protein): pLDDT 76.79, 26% of residues very-high.

**23 experimental structure(s)** (PDB): [4L6Q](https://www.rcsb.org/structure/4L6Q), [4WOT](https://www.rcsb.org/structure/4WOT), [5U7Q](https://www.rcsb.org/structure/5U7Q), [5U7R](https://www.rcsb.org/structure/5U7R), [6ED6](https://www.rcsb.org/structure/6ED6), [6P5M](https://www.rcsb.org/structure/6P5M).

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

*Describes the biological roles of ROCK2 (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:** ROCK2's established molecular role includes protease binding. p.Asp601Val falls in the interaction with ppp1r12a region. In Reactome, ROCK2 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** ROCK2 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

ROCK2 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [EPHA-mediated growth cone collapse](https://reactome.org/content/detail/R-HSA-3928663) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [RHO GTPases Activate ROCKs](https://reactome.org/content/detail/R-HSA-5627117) | electronic |
| [Sema4D induced cell migration and growth-cone collapse](https://reactome.org/content/detail/R-HSA-416572) | electronic |

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

**Molecular function:** protease binding, RNA binding, protein serine/threonine kinase activity, endopeptidase activator activity, Rho-dependent protein serine/threonine kinase activity.

**Biological process:** protein phosphorylation, Rho protein signal transduction, negative regulation of angiogenesis, positive regulation of cell migration, host-mediated perturbation of viral process, negative regulation of nitric oxide biosynthetic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (1 Benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Rare Disease Group, Clinical Genetics, Karolinska Institutet | Uncertain significance | criteria provided, single submitter | research | 2026-04-01 |

## Associated conditions {#conditions}

[volvulus of midgut](https://sugi.bio/atlas/disease/volvulus-of-midgut/).

**Reported phenotype names (ClinVar):** Intestinal malrotation, not specified, AllHighlyPenetrant, INTESTINAL MALROTATION, FAMILIAL, Volvulus of midgut, Congenital malrotation of intestine.

## Similar variants {#similar}

Related ROCK2 variant pages (same residue, condition, or type): [ROCK2 c.3609-11A>C](/variant/rock2-c-3609-minus-11a-c), [ROCK2 p.Thr431Asn](/variant/rock2-p-thr431asn), [ROCK2 p.Ala1013Thr](/variant/rock2-p-ala1013thr), [ROCK2 p.Ala1018Thr](/variant/rock2-p-ala1018thr), [ROCK2 p.Ala663Thr](/variant/rock2-p-ala663thr), [ROCK2 p.Ala663Val](/variant/rock2-p-ala663val), [ROCK2 p.Arg1044Ter](/variant/rock2-p-arg1044ter), [ROCK2 p.Arg1050His](/variant/rock2-p-arg1050his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1686313). 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.*