# NM_000537.4(REN):c.741C>T (p.Ser247=)

https://sugi.bio/variant/ren-p-ser247

## Summary

**REN p.Ser247= (c.741C>T)** is classified **Likely benign** in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-15). Very rare (popmax 0.00446%, eas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the REN gene that is classified as likely benign — not considered disease-causing, 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 | [REN](https://sugi.bio/atlas/gene/REN/) |
| Protein change (HGVS p.) | p.Ser247= |
| Coding change (HGVS c.) | c.741C>T |
| MANE Select transcript | [NM_000537](https://www.ncbi.nlm.nih.gov/nuccore/NM_000537) |
| Variant type | single nucleotide variant |
| Location | chr1:204156754-204156754 (GRCh38) |
| ClinVar | [VCV4929571](https://www.ncbi.nlm.nih.gov/clinvar/variation/4929571/) |

**All HGVS expressions:** `NC_000001.10:g.204125882G>A`, `NC_000001.11:g.204156754G>A`, `NG_012122.1:g.14584C>T`, `NM_000537.4:c.741C>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 (below), not from a missing predictor score.
- Conservation: phyloP -6.652, GERP -3.68 — fast-evolving / accelerated position
- CADD: **PHRED 1.04**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.31 acceptor loss), 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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,882 in the highest group · 7/1,613,666 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,441 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,233 |
| European (non-Finnish) | 0.000254% | 393,269 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-01-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-15 |

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

## Similar variants {#similar}

Related REN variant pages (same residue, condition, or type): [REN p.Ser247Arg](/variant/ren-p-ser247arg), [REN c.249+1G>A](/variant/ren-c-249-plus-1g-a), [REN p.Arg49Ter](/variant/ren-p-arg49ter), [REN p.Lys139Ter](/variant/ren-p-lys139ter), [REN p.Ala182Thr](/variant/ren-p-ala182thr), [REN p.Arg119Cys](/variant/ren-p-arg119cys), [REN p.Arg119His](/variant/ren-p-arg119his), [REN p.Arg148His](/variant/ren-p-arg148his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4929571). 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.*