# NM_033637.4(BTRC):c.510G>A (p.Ser170=)

https://sugi.bio/variant/btrc-p-ser170

## Summary

**BTRC p.Ser170= (c.510G>A)** is classified **Likely benign** in BTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-22). Ultra-rare (popmax 0.0165%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs527330134 · 1 submitter · ultra-rare (popmax 0.0165%, sas)

## For patients & families {#patients}

This is a change in the BTRC 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 | [BTRC](https://sugi.bio/atlas/gene/BTRC/) |
| Protein change (HGVS p.) | p.Ser170= |
| Coding change (HGVS c.) | c.510G>A |
| MANE Select transcript | [NM_033637](https://www.ncbi.nlm.nih.gov/nuccore/NM_033637) |
| dbSNP | [rs527330134](https://www.ncbi.nlm.nih.gov/snp/rs527330134/) |
| Variant type | single nucleotide variant |
| Location | chr10:101521824-101521824 (GRCh38) |
| ClinVar | [VCV2888864](https://www.ncbi.nlm.nih.gov/clinvar/variation/2888864/) |

**All HGVS expressions:** `NC_000010.10:g.103281581G>A`, `NC_000010.11:g.101521824G>A`, `NG_009234.1:g.172757G>A`, `NM_001256856.2:c.432G>A`, `NM_003939.5:c.402G>A`, `NM_033637.4:c.510G>A`

## 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 -8.875, GERP -5.54 — fast-evolving / accelerated position
- CADD: **PHRED 1.137**. 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 **0.0165%** (sas) · FAF95 0.0101% · FAF99 0.00811% · 15/91,062 in the highest group · 53/1,613,834 alleles overall — ultra-rare (popmax 0.0165%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0165% | 6,071 |
| East Asian | 0.0134% | 7,477 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,834 |
| Admixed American | 0.00333% | 29,994 |
| Finnish (not grpmax-eligible) | 0.00313% | 31,993 |
| European (non-Finnish) | 0.00203% | 49,162 |
| African / African-American | 0.00133% | 74,972 |

*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}

**BTRC** population constraint: LOEUF 0.643, pLI 0.001872, missense-Z 2.0569. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **170** lies in an α-helix; the 'homodimerization domain d' region.

AlphaFold model confidence (whole protein): pLDDT 80.33, 63% of residues very-high.

**15 experimental structure(s)** (PDB): [1P22](https://www.rcsb.org/structure/1P22), [2P64](https://www.rcsb.org/structure/2P64), [6M90](https://www.rcsb.org/structure/6M90), [6M91](https://www.rcsb.org/structure/6M91), [6M92](https://www.rcsb.org/structure/6M92), [6M93](https://www.rcsb.org/structure/6M93).

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

*Describes the biological roles of BTRC (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:** BTRC's established molecular role includes beta-catenin binding. p.Ser170= falls in the homodimerization domain d region. In Reactome, BTRC is annotated in disease pathway(s) including **Vpu mediated degradation of CD4**.

**Disease mechanism (Reactome):** BTRC loss or alteration is curated in [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534).

### Pathways affected {#pathways}

BTRC participates in **23 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | 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 |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2](https://reactome.org/content/detail/R-HSA-9762114) | curated |
| [GSK3B-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929356) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [MAP3K8 (TPL2)-dependent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-5684264) | curated |
| [NIK-->noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5676590) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Prolactin receptor signaling](https://reactome.org/content/detail/R-HSA-1170546) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [SCF-beta-TrCP mediated degradation of Emi1](https://reactome.org/content/detail/R-HSA-174113) | curated |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | curated |
| [Degradation of CRY and PER proteins](https://reactome.org/content/detail/R-HSA-9932298) | electronic |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |

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

**Molecular function:** beta-catenin binding, ubiquitin-like ligase-substrate adaptor activity, ubiquitin ligase activator activity.

**Biological process:** protein polyubiquitination, ubiquitin-dependent protein catabolic process, protein ubiquitination, SCF-dependent proteasomal ubiquitin-dependent protein catabolic process, non-canonical NF-kappaB signal transduction, regulation of circadian rhythm.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-22.

**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 | 2022-10-22 |

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

## Similar variants {#similar}

Related BTRC variant pages (same residue, condition, or type): [BTRC p.Leu271Phe](/variant/btrc-p-leu271phe), [BTRC p.Leu86Phe](/variant/btrc-p-leu86phe), [BTRC c.556+7C>G](/variant/btrc-c-556-plus-7c-g), [BTRC p.Ala543Ser](/variant/btrc-p-ala543ser), [BTRC p.Ile229=](/variant/btrc-p-ile229), [BTRC p.Leu387=](/variant/btrc-p-leu387), [BTRC p.Pro592Arg](/variant/btrc-p-pro592arg), [BTRC p.Pro592His](/variant/btrc-p-pro592his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2888864). 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.*