# NM_000537.4(REN):c.399G>T (p.Ser133=)

https://sugi.bio/variant/ren-p-ser133

## Summary

**REN p.Ser133= (c.399G>T)** is classified **Uncertain significance** in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). Very rare (popmax 0.00935%, afr); Associated with renal tubular dysgenesis of genetic origin.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · very rare (popmax 0.00935%, afr)

## For patients & families {#patients}

This is a change in the REN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to renal tubular dysgenesis of genetic origin.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016854/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [REN](https://sugi.bio/atlas/gene/REN/) |
| Protein change (HGVS p.) | p.Ser133= |
| Coding change (HGVS c.) | c.399G>T |
| MANE Select transcript | [NM_001363642](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363642) (variant reported on NM_000537) |
| Variant type | single nucleotide variant |
| Location | chr1:204160653-204160653 (GRCh38) |
| ClinVar | [VCV3578072](https://www.ncbi.nlm.nih.gov/clinvar/variation/3578072/) |

**All HGVS expressions:** `NC_000001.10:g.204129781C>A`, `NC_000001.11:g.204160653C>A`, `NG_012122.1:g.10685G>T`, `NM_000537.4:c.399G>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.62) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -3.653, GERP -3.61 — fast-evolving / accelerated position
- CADD: **PHRED 14.06**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.19**, donor loss **0.00**, acceptor gain **0.62**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.19**, donor loss **0.00**, acceptor gain **0.62**, donor gain **0.00**.
- Pangolin: Δ**0.54** (gain), gain 0.54 / loss 0.35. 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 **0.00935%** (afr) · FAF95 0.00437% · FAF99 0.00309% · 7/74,900 in the highest group · 7/1,613,846 alleles overall — very rare (popmax 0.00935%, afr).

*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}


Curated gene–disease validity (ClinGen):

- **renal tubular dysgenesis of genetic origin** — Definitive (AR)
- **familial juvenile hyperuricemic nephropathy type 2** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.00, 56% of residues very-high.

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

*Describes the biological roles of REN (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:** REN's established molecular role includes identical protein binding.


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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-29 |

## Associated conditions {#conditions}

[renal tubular dysgenesis of genetic origin](https://sugi.bio/atlas/disease/renal-tubular-dysgenesis-of-genetic-origin/), [familial juvenile hyperuricemic nephropathy type 2](https://sugi.bio/atlas/disease/familial-juvenile-hyperuricemic-nephropathy-type-2/).

**Reported phenotype names (ClinVar):** Renal tubular dysgenesis of genetic origin, Familial juvenile hyperuricemic nephropathy type 2, PRIMITIVE RENAL TUBULE SYNDROME, Autosomal Dominant Tubulointerstitial Kidney Disease – REN, EARLY-ONSET HYPERURICEMIA, ANEMIA, AND PROGRESSIVE KIDNEY FAILURE.

## Similar variants {#similar}

Related REN variant pages (same residue, condition, or type): [REN p.Ser133Leu](/variant/ren-p-ser133leu), [REN c.249+1G>A](/variant/ren-c-249-plus-1g-a), [REN p.Arg49Ter](/variant/ren-p-arg49ter), [REN p.Ala182Thr](/variant/ren-p-ala182thr), [REN p.Arg119Cys](/variant/ren-p-arg119cys), [REN p.Arg387Gln](/variant/ren-p-arg387gln), [REN p.Arg395Trp](/variant/ren-p-arg395trp), [REN p.Arg406Cys](/variant/ren-p-arg406cys).

### 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 3578072). 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.*