Is ESRRB p.Arg403Cys (c.1207C>T) pathogenic?

ESRRB p.Arg403Cys (c.1207C>T) is classified Conflicting classifications of pathogenicity in ESRRB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-04-15). Rare (popmax 0.706%, eas); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Arg403Cys (c.1207C>T)?

ESRRB p.Arg403Cys (c.1207C>T) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Arg403Cys (c.1207C>T) in the general population?

ESRRB p.Arg403Cys (c.1207C>T) is rare (popmax 0.706%, eas) (gnomAD).

ESRRB p.Arg403Cys

c.1207C>T · rs373131497 · VCV225349

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.706%, eas)

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	0.709	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 122 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.706% East Asian · 317/44,872 alleles

Filtering AF 0.642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.617%

Overall 0.0209% 338/1,613,602 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.706%	142
Remaining individualsnot grpmax-eligible	0.0112%	8,928
African / African-American	0.00666%	15,012
South Asian	0.0011%	91,060
European (non-Finnish)	0.000678%	147,494

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.Arg403Cys
Coding: c.1207C>T
MANE Select: NM_001379180
dbSNP: rs373131497
Type: single nucleotide variant
Location: chr14:76498300 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 403: the nr lbd domain; an α-helix; 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 p.Arg403His Likely benign ★★ 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-arg403cys (accessed [today's date]).

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