Is ESRRB p.Thr423fs (c.1268_1272del) pathogenic?

ESRRB p.Thr423fs (c.12681272del) is classified Likely pathogenic in ESRRB (ClinVar, Single submitter, 1 submitter; last evaluated 2013-06-02). Absent from gnomAD; Associated with Rare genetic deafness.

What condition is associated with ESRRB p.Thr423fs (c.1268_1272del)?

ESRRB p.Thr423fs (c.1268_1272del) is associated with Rare genetic deafness (ClinVar).

How common is ESRRB p.Thr423fs (c.1268_1272del) in the general population?

ESRRB p.Thr423fs (c.1268_1272del) is absent from gnomAD (gnomAD).

ESRRB p.Thr423fs

c.1268_1272del · rs727504577 · VCV178970

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Rare genetic deafness

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, phastCons 1
Region caveats
Repeat context	tandem	(GCTGCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ESRRB
Protein: p.Thr423fs
Coding: c.1268_1272del
MANE Select: NM_001379180
dbSNP: rs727504577
Type: Deletion
Location: chr14:76498361 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 423: 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

Rare genetic deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESRRB p.Thr423Met Uncertain significance ★★ same residue
ESRRB p.? Likely pathogenic ★ same condition
ESRRB p.Thr423= Likely benign ★ same residue
ESRRB p.Leu338fs Likely pathogenic ★ same condition
ESRRB p.Trp408Ter Likely pathogenic ★ same condition
ESRRB p.Val363fs Likely pathogenic ★ same condition
ESRRB p.Pro251fs Pathogenic ★ same type
ESRRB p.Leu420fs Uncertain significance ★ same type

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-thr423fs (accessed [today's date]).

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