Is ESRRB p.Pro407Ser (c.1219C>T) pathogenic?

ESRRB p.Pro407Ser (c.1219C>T) is classified Benign/Likely benign in ESRRB (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Pro407Ser (c.1219C>T)?

ESRRB p.Pro407Ser (c.1219C>T) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

ESRRB p.Pro407Ser

Q: How common is ESRRB p.Pro407Ser (c.1219C>T) in the general population?

ESRRB p.Pro407Ser (c.1219C>T) is common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1219C>T · rs61742642 · VCV44995

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele

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	0.681	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 122 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.4% Admixed American · 8,055/59,898 alleles

Filtering AF 13.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.1%

Overall 7.03% 113,415/1,613,184 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	13.4%	7
East Asian	9.67%	10
Amishnot grpmax-eligible	7.24%	14
European (non-Finnish)	7.07%	14
Remaining individualsnot grpmax-eligible	7.04%	14
South Asian	6.8%	15
Ashkenazi Jewishnot grpmax-eligible	5.58%	18
Middle Eastern	5.3%	19
Finnishnot grpmax-eligible	5.21%	19
African / African-American	2.3%	43

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.Pro407Ser
Coding: c.1219C>T
MANE Select: NM_001379180
dbSNP: rs61742642
Type: single nucleotide variant
Location: chr14:76498312 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 407: 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 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-pro407ser (accessed [today's date]).

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