# NM_182706.5(SCRIB):c.1126G>A (p.Ala376Thr)

https://sugi.bio/variant/scrib-p-ala376thr

## Summary

**SCRIB p.Ala376Thr (c.1126G>A)** is classified **Uncertain significance** in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1137); Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## 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.Ala376Thr |
| Coding change (HGVS c.) | c.1126G>A |
| MANE Select transcript | [NM_182706](https://www.ncbi.nlm.nih.gov/nuccore/NM_182706) |
| Variant type | single nucleotide variant |
| Location | chr8:143811053-143811053 (GRCh38) |
| ClinVar | [VCV3793342](https://www.ncbi.nlm.nih.gov/clinvar/variation/3793342/) |

**All HGVS expressions:** `NC_000008.10:g.144893223C>T`, `NC_000008.11:g.143811053C>T`, `NG_030583.1:g.9327G>A`, `NG_030583.2:g.9720G>A`, `NM_015356.5:c.1126G>A`, `NM_182706.5:c.1126G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1137)
- REVEL 0.282 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.143 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.863, GERP -3.97, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.0**. 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 0.87** across the covering region of the MANE Select transcript (143,810,925–143,815,372), spanning 4,447 bp. Chi-square p 0.0026. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**.
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.06. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,550 in the highest group · 2/1,612,028 alleles overall — very rare (popmax 0.00017%, nfe).

*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 **376** lies in the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' 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.Ala376Thr falls in the sufficient for targeting to adherens junction and to inhibit cell proliferation region.


### 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 2025-02-08.

**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 | 2025-02-08 |

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

## Similar variants {#similar}

Related SCRIB variant pages (same residue, condition, or type): [SCRIB p.Ala376=](/variant/scrib-p-ala376), [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).

### 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 3793342). 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.*