Is ESRRB p.Ser59= (c.177G>A) pathogenic?

ESRRB p.Ser59= (c.177G>A) is classified Conflicting classifications of pathogenicity in ESRRB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-20). Rare (popmax 0.167%, amr); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Ser59= (c.177G>A)?

ESRRB p.Ser59= (c.177G>A) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Ser59= (c.177G>A) in the general population?

ESRRB p.Ser59= (c.177G>A) is rare (popmax 0.167%, amr) (gnomAD).

ESRRB p.Ser59=

c.177G>A · rs781612689 · VCV314481

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.167%, amr)

Conditions

autosomal recessive nonsyndromic hearing loss 35

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -3.7
Overall
CADD	9.735	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.167% Admixed American · 100/59,834 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.131%

Overall 0.0077% 124/1,610,502 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.167%	598
East Asian	0.0246%	4,067
Remaining individualsnot grpmax-eligible	0.0112%	8,908
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,468
European (non-Finnish)	0.000424%	235,886

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.Ser59=
Coding: c.177G>A
MANE Select: NM_001379180
dbSNP: rs781612689
Type: single nucleotide variant
Location: chr14:76439467 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB

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-ser59 (accessed [today's date]).

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