Is ESRRB p.Ile48= (c.144C>A) pathogenic?

ESRRB p.Ile48= (c.144C>A) is classified Benign in ESRRB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 24.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 35.

What condition is associated with ESRRB p.Ile48= (c.144C>A)?

ESRRB p.Ile48= (c.144C>A) is associated with autosomal recessive nonsyndromic hearing loss 35 (ClinVar).

ESRRB p.Ile48=

Q: How common is ESRRB p.Ile48= (c.144C>A) in the general population?

ESRRB p.Ile48= (c.144C>A) is common (popmax 24.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.144C>A · rs35544003 · VCV45001

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 24.8%, eas) — 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.5, phastCons 0.001
Overall
CADD	4.372	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 24.8% East Asian · 11,141/44,850 alleles

Filtering AF 24.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.3%

Overall 6.47% 104,414/1,613,444 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	24.8%	4
South Asian	13.4%	7
African / African-American	9.14%	11
Admixed American	8.77%	11
Remaining individualsnot grpmax-eligible	7.18%	14
Amishnot grpmax-eligible	6.03%	17
Finnishnot grpmax-eligible	5.79%	17
European (non-Finnish)	5.07%	20
Middle Eastern	3.55%	28
Ashkenazi Jewishnot grpmax-eligible	2.45%	41

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.Ile48=
Coding: c.144C>A
MANE Select: NM_001379180
dbSNP: rs35544003
Type: single nucleotide variant
Location: chr14:76439434 (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-ile48 (accessed [today's date]).

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