# NM_014306.5(RTCB):c.1114G>A (p.Val372Ile)

https://sugi.bio/variant/rtcb-p-val372ile

## Summary

**RTCB p.Val372Ile (c.1114G>A)** is classified **Uncertain significance** in RTCB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1426); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2518021113 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RTCB 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 | [RTCB](https://sugi.bio/atlas/gene/RTCB/) |
| Protein change (HGVS p.) | p.Val372Ile |
| Coding change (HGVS c.) | c.1114G>A |
| MANE Select transcript | [NM_014306](https://www.ncbi.nlm.nih.gov/nuccore/NM_014306) |
| dbSNP | [rs2518021113](https://www.ncbi.nlm.nih.gov/snp/rs2518021113/) |
| Variant type | single nucleotide variant |
| Location | chr22:32395091-32395091 (GRCh38) |
| ClinVar | [VCV2492260](https://www.ncbi.nlm.nih.gov/clinvar/variation/2492260/) |

**All HGVS expressions:** `NC_000022.10:g.32791078C>T`, `NC_000022.11:g.32395091C>T`, `NM_014306.5:c.1114G>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** (0.1426)
- REVEL 0.202 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.726 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.55) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.588, GERP 1.53, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.0**. 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 0.85** across the covering region of the MANE Select transcript (32,387,995–32,396,224), spanning 8,229 bp. Chi-square p 0.0093. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.55**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.55**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**RTCB** population constraint: LOEUF 0.622, pLI 0.16535, missense-Z 2.0457. *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 **372** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 95.66, 89% of residues very-high.

**5 experimental structure(s)** (PDB): [7P3B](https://www.rcsb.org/structure/7P3B), [8BTT](https://www.rcsb.org/structure/8BTT), [8ODO](https://www.rcsb.org/structure/8ODO), [8ODP](https://www.rcsb.org/structure/8ODP), [8ORJ](https://www.rcsb.org/structure/8ORJ).

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

*Describes the biological roles of RTCB (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:** RTCB's established molecular role includes RNA binding.


### Pathways affected {#pathways}

RTCB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |

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

**Molecular function:** RNA binding, vinculin binding, RNA ligase (GTP) activity.

**Biological process:** RNA splicing, via endonucleolytic cleavage and ligation, tRNA exon ligation, tRNA splicing, via endonucleolytic cleavage and ligation, IRE1-mediated unfolded protein response, mRNA splicing, via endonucleolytic cleavage and ligation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-01.

**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 | 2023-03-01 |

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

## Similar variants {#similar}

Related RTCB variant pages (same residue, condition, or type): [RTCB p.Ala276=](/variant/rtcb-p-ala276), [RTCB p.Val347=](/variant/rtcb-p-val347), [RTCB p.Ala101Thr](/variant/rtcb-p-ala101thr), [RTCB p.Ala211Val](/variant/rtcb-p-ala211val), [RTCB p.Ala242Ser](/variant/rtcb-p-ala242ser), [RTCB p.Ala294Val](/variant/rtcb-p-ala294val), [RTCB p.Ala296Thr](/variant/rtcb-p-ala296thr), [RTCB p.Ala333Ser](/variant/rtcb-p-ala333ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2492260). 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.*