Is ESRRB p.Ala69Val (c.206C>T) pathogenic?

ESRRB p.Ala69Val (c.206C>T) is classified Conflicting classifications of pathogenicity in ESRRB (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-27). Rare (popmax 0.564%, afr); Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Ala69Val (c.206C>T)?

ESRRB p.Ala69Val (c.206C>T) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

How common is ESRRB p.Ala69Val (c.206C>T) in the general population?

ESRRB p.Ala69Val (c.206C>T) is rare (popmax 0.564%, afr) (gnomAD).

ESRRB p.Ala69Val

c.206C>T · rs61760172 · VCV178342

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.564%, afr)

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	0.272	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.79, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 122 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	18.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.564% African / African-American · 423/75,060 alleles

Filtering AF 0.519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.502%

Overall 0.0301% 486/1,612,634 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.564%	177
Remaining individualsnot grpmax-eligible	0.032%	3,124
Admixed American	0.03%	3,334
South Asian	0.00659%	15,178
European (non-Finnish)	0.00161%	62,100

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.Ala69Val
Coding: c.206C>T
MANE Select: NM_001379180
dbSNP: rs61760172
Type: single nucleotide variant
Location: chr14:76439496 (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-ala69val (accessed [today's date]).

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