Is ESRRB p.Arg173His (c.518G>A) pathogenic?

ESRRB p.Arg173His (c.518G>A) is classified Conflicting classifications of pathogenicity in ESRRB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-24). Very rare (popmax 0.00329%, sas); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Arg173His (c.518G>A)?

ESRRB p.Arg173His (c.518G>A) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Arg173His (c.518G>A) in the general population?

ESRRB p.Arg173His (c.518G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

ESRRB p.Arg173His

c.518G>A · VCV3601085

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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	0.949	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00274% 40/1,461,772 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00938%	10,666
Remaining individualsnot grpmax-eligible	0.008%	12,499
South Asiangrpmax	0.00329%	30,361
European (non-Finnish)	0.0022%	45,384

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg173His
Coding: c.518G>A
MANE Select: NM_001379180
Type: single nucleotide variant
Location: chr14:76462602 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 173: 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.Arg173Cys 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-arg173his (accessed [today's date]).

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