# NM_021975.4(RELA):c.507A>C (p.Ser169=)

https://sugi.bio/variant/rela-p-ser169

## Summary

**RELA p.Ser169= (c.507A>C)** is classified **Likely benign** in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). Very rare (popmax 0.00801%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1159652903 · 1 submitter · very rare (popmax 0.00801%, afr)

## 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.Ser169= |
| Coding change (HGVS c.) | c.507A>C |
| MANE Select transcript | [NM_021975](https://www.ncbi.nlm.nih.gov/nuccore/NM_021975) |
| dbSNP | [rs1159652903](https://www.ncbi.nlm.nih.gov/snp/rs1159652903/) |
| Variant type | single nucleotide variant |
| Location | chr11:65659718-65659718 (GRCh38) |
| ClinVar | [VCV2805223](https://www.ncbi.nlm.nih.gov/clinvar/variation/2805223/) |

**All HGVS expressions:** `NC_000011.10:g.65659718T>G`, `NC_000011.9:g.65427189T>G`, `NG_029971.1:g.8255A>C`, `NM_001145138.2:c.498A>C`, `NM_001243984.2:c.507A>C`, `NM_001243985.2:c.507A>C`, `NM_001404657.1:c.540A>C`, `NM_001404658.1:c.480A>C`, `NM_001404659.1:c.507A>C`, `NM_001404660.1:c.507A>C`, `NM_001404661.1:c.126A>C`, `NM_001404662.1:c.414A>C`, `NM_001404663.1:c.414A>C`, `NM_021975.4:c.507A>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 (below), not from a missing predictor score.
- Conservation: phyloP -1.448, GERP -3.57 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.97**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00228% · 6/74,938 in the highest group · 6/1,613,822 alleles overall — very rare (popmax 0.00801%, 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}

**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 **169** 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.Ser169= 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 2023-07-28.

**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 | 2023-07-28 |

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

## Same-residue context {#hotspot}

Residue **169** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RELA p.Ser169Ter](/variant/rela-p-ser169ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RELA variant pages (same residue, condition, or type): [RELA p.Ser169Ter](/variant/rela-p-ser169ter), [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).

### 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 2805223). 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.*