Is ESRRB p.Arg180His (c.539G>A) pathogenic?

ESRRB p.Arg180His (c.539G>A) is classified Uncertain significance in ESRRB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-27). Very rare (popmax 0.000339%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Arg180His (c.539G>A)?

ESRRB p.Arg180His (c.539G>A) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Arg180His (c.539G>A) in the general population?

ESRRB p.Arg180His (c.539G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

ESRRB p.Arg180His

c.539G>A · rs763549223 · VCV1978091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.971	strongly pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 122 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,930 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,722 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ESRRB
Protein: p.Arg180His
Coding: c.539G>A
MANE Select: NM_001379180
dbSNP: rs763549223
Type: single nucleotide variant
Location: chr14:76462623 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 180: a DNA-binding region; the 'interaction with nanog' region

Full ESRRB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 35 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESRRB p.Arg180Cys Uncertain significance ★★ same residue
ESRRB c.*1451C>G Likely pathogenic ★★ same condition
ESRRB c.578-4A>G Uncertain significance ★★ same condition
ESRRB c.*1502A>T Uncertain significance ★★ same condition
ESRRB c.*1604G>A Uncertain significance ★★ same condition
ESRRB c.*2334G>A Uncertain significance ★★ same condition
ESRRB c.*2382G>A Uncertain significance ★★ same condition
ESRRB p.Ala101Val Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/esrrb-p-arg180his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown