# NM_001379180.1(ESRRB):c.1219C>T (p.Pro407Ser)

https://sugi.bio/variant/esrrb-p-pro407ser

## Summary

**ESRRB p.Pro407Ser (c.1219C>T)** is classified **Benign/Likely benign** in ESRRB (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 35.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61742642 · 9 submitters · 1 linked condition · common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ESRRB gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 35.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022609/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ESRRB](https://sugi.bio/atlas/gene/ESRRB/) |
| Protein change (HGVS p.) | p.Pro407Ser |
| Coding change (HGVS c.) | c.1219C>T |
| MANE Select transcript | [NM_001379180](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379180) |
| dbSNP | [rs61742642](https://www.ncbi.nlm.nih.gov/snp/rs61742642/) |
| Variant type | single nucleotide variant |
| Location | chr14:76498312-76498312 (GRCh38) |
| ClinVar | [VCV44995](https://www.ncbi.nlm.nih.gov/clinvar/variation/44995/) |

**All HGVS expressions:** `NC_000014.8:g.76964655C>T`, `NC_000014.9:g.76498312C>T`, `NG_012278.2:g.131966C>T`, `NM_001379180.1:c.1219C>T`, `NM_004452.4:c.1156C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 7.63, GERP 2.19, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.3**. 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 0.80** across the covering region of the MANE Select transcript (76,376,402–76,498,455), spanning 122,053 bp. Chi-square p 1.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **13.4%** (amr) · FAF95 13.2% · FAF99 13.1% · 8,055/59,898 in the highest group · 113,415/1,613,184 alleles overall — common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 13.4% | 7 |
| East Asian | 9.67% | 10 |
| Amish (not grpmax-eligible) | 7.24% | 14 |
| European (non-Finnish) | 7.07% | 14 |
| Remaining individuals (not grpmax-eligible) | 7.04% | 14 |
| South Asian | 6.8% | 15 |
| Ashkenazi Jewish (not grpmax-eligible) | 5.58% | 18 |
| Middle Eastern | 5.3% | 19 |
| Finnish (not grpmax-eligible) | 5.21% | 19 |
| African / African-American | 2.3% | 43 |

*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}

**ESRRB** population constraint: LOEUF 0.56, pLI 0.79243, missense-Z 1.791. *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):

- **nonsyndromic genetic hearing loss** — Definitive (AR)

## Protein context {#protein}

Residue **407** lies in the nr lbd domain; an α-helix; the 'essential for esrrb transcriptional activity and interaction with ncoa3' region.

AlphaFold model confidence (whole protein): pLDDT 79.14, 62% of residues very-high.

**3 experimental structure(s)** (PDB): [1LO1](https://www.rcsb.org/structure/1LO1), [6LIT](https://www.rcsb.org/structure/6LIT), [6LN4](https://www.rcsb.org/structure/6LN4).

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

*Describes the biological roles of ESRRB (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:** ESRRB's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Pro407Ser falls in the nr lbd domain.


### Pathways affected {#pathways}

ESRRB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |

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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, sequence-specific DNA binding, sequence-specific double-stranded DNA binding.

**Biological process:** regulation of DNA-templated transcription, cell population proliferation, stem cell population maintenance.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 2 Likely benign).

**Submission history:** 9 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2020-10-02 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2012-05-07 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-09-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-05-09 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2023-11-29 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 35](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-35/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 35, not specified, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related ESRRB variant pages (same residue, condition, or type): [ESRRB c.*1451C>G](/variant/esrrb-c-star-1451c-g), [ESRRB c.578-4A>G](/variant/esrrb-c-578-minus-4a-g), [ESRRB c.*1502A>T](/variant/esrrb-c-star-1502a-t), [ESRRB c.*1604G>A](/variant/esrrb-c-star-1604g-a), [ESRRB c.*2334G>A](/variant/esrrb-c-star-2334g-a), [ESRRB c.*2382G>A](/variant/esrrb-c-star-2382g-a), [ESRRB p.Ala101Val](/variant/esrrb-p-ala101val), [ESRRB p.Arg180His](/variant/esrrb-p-arg180his).

### 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 44995). 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.*