# NM_007212.4(RNF2):c.246T>G (p.Ser82Arg)

https://sugi.bio/variant/rnf2-p-ser82arg

## Summary

**RNF2 p.Ser82Arg (c.246T>G)** is classified **Pathogenic** in RNF2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-08-19). AlphaMissense: likely pathogenic (0.9971); Absent from gnomAD v4.1; Associated with Luo-Schoch-Yamamoto syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1651768254 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RNF2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Luo-Schoch-Yamamoto syndrome.

*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 | [RNF2](https://sugi.bio/atlas/gene/RNF2/) |
| Protein change (HGVS p.) | p.Ser82Arg |
| Coding change (HGVS c.) | c.246T>G |
| MANE Select transcript | [NM_007212](https://www.ncbi.nlm.nih.gov/nuccore/NM_007212) |
| dbSNP | [rs1651768254](https://www.ncbi.nlm.nih.gov/snp/rs1651768254/) |
| Variant type | single nucleotide variant |
| Location | chr1:185091737-185091737 (GRCh38) |
| ClinVar | [VCV1189036](https://www.ncbi.nlm.nih.gov/clinvar/variation/1189036/) |

**All HGVS expressions:** `NC_000001.10:g.185060869T>G`, `NC_000001.11:g.185091737T>G`, `NM_007212.4:c.246T>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9971) — concordant with the pathogenic call
- REVEL 0.595 (indeterminate)
- SaProt LLR -11.828 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.62) — consistent with the pathogenic call
- Conservation: phyloP 0.475, GERP -1.98, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 24.8**. 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 0.10** across the covering region of the MANE Select transcript (185,091,700–185,093,119), spanning 1,419 bp — the region is depleted of missense variation. Chi-square p 1.3e-08. 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 **0.62**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.04**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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}

**RNF2** population constraint: LOEUF 0.321, pLI 0.99993, missense-Z 2.9682; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **BAP1-related tumor predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **82** lies in a UniProt-annotated variant site (in lusyam; uncertain significance); the 'interaction with hip2' region; a turn.

AlphaFold model confidence (whole protein): pLDDT 78.27, 44% of residues very-high.

**28 experimental structure(s)** (PDB): [28OE](https://www.rcsb.org/structure/28OE), [2H0D](https://www.rcsb.org/structure/2H0D), [3GS2](https://www.rcsb.org/structure/3GS2), [3H8H](https://www.rcsb.org/structure/3H8H), [3IXS](https://www.rcsb.org/structure/3IXS), [3RPG](https://www.rcsb.org/structure/3RPG).

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

*Describes the biological roles of RNF2 (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:** RNF2's established molecular role includes chromatin binding. p.Ser82Arg falls in the interaction with hip2 region.


### Pathways affected {#pathways}

RNF2 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | other |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | other |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | other |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | other |
| [SUMOylation of DNA methylation proteins](https://reactome.org/content/detail/R-HSA-4655427) | other |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | other |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | other |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | other |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | other |

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

**Molecular function:** chromatin binding, zinc ion binding, RING-like zinc finger domain binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, epigenetic regulation of gene expression.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-08-19.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2021-08-19 |

## Associated conditions {#conditions}

[Luo-Schoch-Yamamoto syndrome](https://sugi.bio/atlas/disease/luo-schoch-yamamoto-syndrome/).

**Reported phenotype names (ClinVar):** Luo-Schoch-Yamamoto syndrome.

## Similar variants {#similar}

Related RNF2 variant pages (same residue, condition, or type): [BAP1 p.Phe82Cys](/variant/bap1-p-phe82cys), [RNF2 c.465-1G>A](/variant/rnf2-c-465-minus-1g-a), [RNF2 p.Arg70His](/variant/rnf2-p-arg70his), [RNF2 p.Thr197Ile](/variant/rnf2-p-thr197ile), [RNF2 p.Tyr247His](/variant/rnf2-p-tyr247his), [RNF2 p.Val127Ile](/variant/rnf2-p-val127ile), [RNF2 p.Val256Leu](/variant/rnf2-p-val256leu), [RNF2 p.Gln301Arg](/variant/rnf2-p-gln301arg).

### 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 2026-07-14); 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 1189036). 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.*