# NM_182706.5(SCRIB):c.2284C>T (p.Arg762Trp)

https://sugi.bio/variant/scrib-p-arg762trp

## Summary

**SCRIB p.Arg762Trp (c.2284C>T)** is classified **Uncertain significance** in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-16). AlphaMissense: likely pathogenic (0.8846); Very rare (popmax 0.00511%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs782384815 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00511%, amr)

## For patients & families {#patients}

This is a change in the SCRIB 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 | [SCRIB](https://sugi.bio/atlas/gene/SCRIB/) |
| Protein change (HGVS p.) | p.Arg762Trp |
| Coding change (HGVS c.) | c.2284C>T |
| MANE Select transcript | [NM_182706](https://www.ncbi.nlm.nih.gov/nuccore/NM_182706) |
| dbSNP | [rs782384815](https://www.ncbi.nlm.nih.gov/snp/rs782384815/) |
| Variant type | single nucleotide variant |
| Location | chr8:143806469-143806469 (GRCh38) |
| ClinVar | [VCV2278518](https://www.ncbi.nlm.nih.gov/clinvar/variation/2278518/) |

**All HGVS expressions:** `NC_000008.10:g.144888639G>A`, `NC_000008.11:g.143806469G>A`, `NG_030583.1:g.13911C>T`, `NG_030583.2:g.14304C>T`, `NM_015356.5:c.2284C>T`, `NM_182706.5:c.2284C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8846)
- REVEL 0.452 (indeterminate)
- SaProt LLR -15.8 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 8.639, GERP 1.47, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 1.13** across the covering region of the MANE Select transcript (143,791,224–143,810,924), spanning 19,700 bp. Chi-square p 9.1e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.80 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00511%** (amr) · FAF95 0.00136% · FAF99 0.000676% · 3/58,714 in the highest group · 9/1,599,448 alleles overall — very rare (popmax 0.00511%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00511% | 19,571 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00341% | 29,302 |
| East Asian | 0.00226% | 44,208 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,884 |
| European (non-Finnish) | 0.000256% | 390,885 |

*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}

**SCRIB** population constraint: LOEUF 0.684, pLI 8.3323e-12, missense-Z -3.2663. *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 **762** lies in a β-strand; the pdz 1 domain; the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region; the 'interaction with arhgef7' region; the 'required for interaction with vim' region.

AlphaFold model confidence (whole protein): pLDDT 52.33, 0% of residues very-high.

**42 experimental structure(s)** (PDB): [9KFM](https://www.rcsb.org/structure/9KFM), [9KFN](https://www.rcsb.org/structure/9KFN), [9KFO](https://www.rcsb.org/structure/9KFO), [9KQS](https://www.rcsb.org/structure/9KQS), [9UK1](https://www.rcsb.org/structure/9UK1), [9UK3](https://www.rcsb.org/structure/9UK3) — incl. mutant structure 6EEY.

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

*Describes the biological roles of SCRIB (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:** SCRIB's established molecular role includes signaling adaptor activity. p.Arg762Trp falls in the pdz 1 domain.


### Pathways affected {#pathways}

SCRIB participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [RND2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696270) | curated |
| [RND3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696264) | curated |
| [Asymmetric localization of PCP proteins](https://reactome.org/content/detail/R-HSA-4608870) | electronic |

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

**Molecular function:** signaling adaptor activity, cadherin binding.

**Biological process:** negative regulation of translational initiation, neural tube closure, positive regulation of receptor recycling, cell population proliferation, cell migration, polarized epithelial cell differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-16.

**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 | 2022-03-16 |

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

## Similar variants {#similar}

Related SCRIB variant pages (same residue, condition, or type): [SCRIB c.3120+10C>G](/variant/scrib-c-3120-plus-10c-g), [SCRIB c.504-9C>T](/variant/scrib-c-504-minus-9c-t), [SCRIB p.Ala1488=](/variant/scrib-p-ala1488), [SCRIB p.Arg492=](/variant/scrib-p-arg492), [SCRIB p.Asn647=](/variant/scrib-p-asn647), [SCRIB p.Leu254=](/variant/scrib-p-leu254), [SCRIB p.Phe571=](/variant/scrib-p-phe571), [SCRIB p.Pro1343=](/variant/scrib-p-pro1343).

### 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 2278518). 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.*