# NM_021975.4(RELA):c.474G>C (p.Arg158=)

https://sugi.bio/variant/rela-p-arg158

## Summary

**RELA p.Arg158= (c.474G>C)** is classified **Likely benign** in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RELA 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 | [RELA](https://sugi.bio/atlas/gene/RELA/) |
| Protein change (HGVS p.) | p.Arg158= |
| Coding change (HGVS c.) | c.474G>C |
| MANE Select transcript | [NM_021975](https://www.ncbi.nlm.nih.gov/nuccore/NM_021975) |
| Variant type | single nucleotide variant |
| Location | chr11:65659751-65659751 (GRCh38) |
| ClinVar | [VCV3652175](https://www.ncbi.nlm.nih.gov/clinvar/variation/3652175/) |

**All HGVS expressions:** `NC_000011.10:g.65659751C>G`, `NC_000011.9:g.65427222C>G`, `NG_029971.1:g.8222G>C`, `NM_001145138.2:c.465G>C`, `NM_001243984.2:c.474G>C`, `NM_001243985.2:c.474G>C`, `NM_001404657.1:c.507G>C`, `NM_001404658.1:c.447G>C`, `NM_001404659.1:c.474G>C`, `NM_001404660.1:c.474G>C`, `NM_001404661.1:c.93G>C`, `NM_001404662.1:c.381G>C`, `NM_001404663.1:c.381G>C`, `NM_021975.4:c.474G>C`

## 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 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.227, GERP -2.56, phastCons 0.969 — weakly conserved position
- CADD: **PHRED 15.4**. 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 **0.03**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, 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}

**RELA** population constraint: LOEUF 0.4, pLI 0.99992, missense-Z 2.5486. *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):

- **combined immunodeficiency due to RELA haploinsufficiency** — Definitive (AD)

## Protein context {#protein}

Residue **158** lies in the rhd domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 73.52, 49% of residues very-high.

**88 experimental structure(s)** (PDB): [1NFI](https://www.rcsb.org/structure/1NFI), [2LSP](https://www.rcsb.org/structure/2LSP), [2O61](https://www.rcsb.org/structure/2O61), [3GUT](https://www.rcsb.org/structure/3GUT), [3QXY](https://www.rcsb.org/structure/3QXY), [3RC0](https://www.rcsb.org/structure/3RC0).

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

*Describes the biological roles of RELA (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:** RELA's established molecular role includes transcription cis-regulatory region binding. p.Arg158= falls in the rhd domain. In Reactome, RELA is annotated in disease pathway(s) including **IkBA variant leads to EDA-ID**, **Purinergic signaling in leishmaniasis infection**.

**Disease mechanism (Reactome):** RELA loss or alteration is curated in [IkBA variant leads to EDA-ID](https://reactome.org/content/detail/R-HSA-5603029), [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826), [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

RELA participates in **29 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [IkBA variant leads to EDA-ID](https://reactome.org/content/detail/R-HSA-5603029) | curated |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [CLEC7A/inflammasome pathway](https://reactome.org/content/detail/R-HSA-5660668) | curated |
| [DEx/H-box helicases activate type I IFN and inflammatory cytokines production ](https://reactome.org/content/detail/R-HSA-3134963) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [Interleukin-1 processing](https://reactome.org/content/detail/R-HSA-448706) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [NF-kB is activated and signals survival](https://reactome.org/content/detail/R-HSA-209560) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [RIP-mediated NFkB activation via ZBP1](https://reactome.org/content/detail/R-HSA-1810476) | curated |
| [Regulated proteolysis of p75NTR](https://reactome.org/content/detail/R-HSA-193692) | curated |
| [Regulation of NFE2L2 gene expression](https://reactome.org/content/detail/R-HSA-9818749) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [SUMOylation of immune response proteins](https://reactome.org/content/detail/R-HSA-4755510) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | curated |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | curated |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, RNA polymerase II core promoter sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, transcription coactivator binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, defense response to tumor cell, regulation of transcription by RNA polymerase II, inflammatory response, neuropeptide signaling pathway, canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-23 |

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

## Similar variants {#similar}

Related RELA variant pages (same residue, condition, or type): [RELA p.Arg198Ter](/variant/rela-p-arg198ter), [RELA p.Arg236Ter](/variant/rela-p-arg236ter), [RELA p.Arg329Ter](/variant/rela-p-arg329ter), [RELA p.Gln372Ter](/variant/rela-p-gln372ter), [RELA p.Ala264Val](/variant/rela-p-ala264val), [RELA p.Ala404Pro](/variant/rela-p-ala404pro), [RELA p.Ala404Thr](/variant/rela-p-ala404thr), [RELA p.Ala538Thr](/variant/rela-p-ala538thr).

### 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 3652175). 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.*