Is ESRRB p.Arg203His (c.608G>A) pathogenic?

ESRRB p.Arg203His (c.608G>A) is classified Pathogenic in ESRRB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-06-04). Very rare (popmax 0.00439%, sas); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Arg203His (c.608G>A)?

ESRRB p.Arg203His (c.608G>A) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Arg203His (c.608G>A) in the general population?

ESRRB p.Arg203His (c.608G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

ESRRB p.Arg203His

c.608G>A · rs1060499794 · VCV402254

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00439%, 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	0.724	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, 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 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000547% 8/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	0.000339%	295,008

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.Arg203His
Coding: c.608G>A
MANE Select: NM_001379180
dbSNP: rs1060499794
Type: single nucleotide variant
Location: chr14:76482046 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 203: the 'interaction with nanog' region; the 'essential for esrrb transcriptional activity and interaction with ncoa3' 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 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
ESRRB p.Arg180His 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-arg203his (accessed [today's date]).

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