# NM_017999.5(RNF31):c.70del (p.Asp24fs)

https://sugi.bio/variant/rnf31-p-asp24fs

## Summary

**RNF31 p.Asp24fs (c.70del)** is classified **Uncertain significance** in RNF31 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). Very rare (popmax 0.000258%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2038191896 · 1 submitter · very rare (popmax 0.000258%, nfe)

## For patients & families {#patients}

This is a change in the RNF31 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 | [RNF31](https://sugi.bio/atlas/gene/RNF31/) |
| Protein change (HGVS p.) | p.Asp24fs |
| Coding change (HGVS c.) | c.70del |
| MANE Select transcript | [NM_017999](https://www.ncbi.nlm.nih.gov/nuccore/NM_017999) |
| dbSNP | [rs2038191896](https://www.ncbi.nlm.nih.gov/snp/rs2038191896/) |
| Variant type | Deletion |
| Location | chr14:24147766-24147766 (GRCh38) |
| ClinVar | [VCV2855714](https://www.ncbi.nlm.nih.gov/clinvar/variation/2855714/) |

**All HGVS expressions:** `LRG_1315:g.5894del`, `LRG_1315t1:c.70del`, `NC_000014.8:g.24616977del`, `NC_000014.9:g.24147768del`, `NG_042234.1:g.5894del`, `NG_074678.2:g.636del`, `NG_074678.3:g.636del`, `NM_001310332.2:c.-325-208del`, `NM_017999.5:c.70del`

## 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 4.221, GERP 0.579, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.37, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 21**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 21.7**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000258%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,163,948 in the highest group · 3/1,575,246 alleles overall — very rare (popmax 0.000258%, 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}

**RNF31** population constraint: LOEUF 0.37, pLI 1, missense-Z 3.0382. *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):

- **immunodeficiency 115 with autoinflammation** — Moderate (AR)

## Protein context {#protein}

Residue **24** lies in the 'polyubiquitin-binding' region.

AlphaFold model confidence (whole protein): pLDDT 78.39, 34% of residues very-high.

**36 experimental structure(s)** (PDB): [2CT7](https://www.rcsb.org/structure/2CT7), [4DBG](https://www.rcsb.org/structure/4DBG), [4JUY](https://www.rcsb.org/structure/4JUY), [4LJO](https://www.rcsb.org/structure/4LJO), [4LJP](https://www.rcsb.org/structure/4LJP), [4LJQ](https://www.rcsb.org/structure/4LJQ).

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

*Describes the biological roles of RNF31 (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:** RNF31's established molecular role includes ubiquitin-protein transferase activity. p.Asp24fs falls in the polyubiquitin-binding region.


### Pathways affected {#pathways}

RNF31 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | curated |
| [TNFR1-induced proapoptotic signaling](https://reactome.org/content/detail/R-HSA-5357786) | curated |

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

**Molecular function:** ubiquitin-protein transferase activity, ubiquitin protein ligase binding, identical protein binding, ubiquitin binding, ubiquitin protein ligase activity.

**Biological process:** protein polyubiquitination, defense response to bacterium, positive regulation of canonical NF-kappaB signal transduction, T cell receptor signaling pathway, protein linear polyubiquitination, positive regulation of xenophagy.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-06 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RNF31 variant pages (same residue, condition, or type): [RNF31 p.Asp24Gly](/variant/rnf31-p-asp24gly), [RNF31 c.193-2_196del](/variant/rnf31-c-193-minus-2-196del), [RNF31 c.2403+6_2403+9del](/variant/rnf31-c-2403-plus-6-2403-plus-9del), [RNF31 c.340-2del](/variant/rnf31-c-340-minus-2del), [RNF31 p.Arg749_Asp751del](/variant/rnf31-p-arg749-asp751del), [RNF31 p.Asn672_Tyr673insTer](/variant/rnf31-p-asn672-tyr673inster), [RNF31 p.Cys415fs](/variant/rnf31-p-cys415fs), [RNF31 p.Gly474_Pro476del](/variant/rnf31-p-gly474-pro476del).

### 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 2855714). 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.*