Is ESRRB c.577+2T>C pathogenic?

ESRRB c.577+2T>C is classified Likely pathogenic in ESRRB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-03). Very rare (popmax 0.00134%, afr).

How common is ESRRB c.577+2T>C in the general population?

ESRRB c.577+2T>C is very rare (popmax 0.00134%, afr) (gnomAD).

ESRRB c.577+2T>C

VCV3606848

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.84	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Non-coding constraint	Z 2.04	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,788 alleles

Overall 0.000657% 1/152,094 alleles · very rare

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
Coding: c.577+2T>C
MANE Select: NM_001379180
Type: single nucleotide variant
Location: chr14:76462663 (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

Similar variants

ESRRB c.851-2A>T Likely pathogenic ★★ same type
ESRRB c.*1451C>G Likely pathogenic ★★ same type
ESRRB p.Arg270Ter Likely pathogenic ★★ same type
ESRRB c.578-4A>G Uncertain significance ★★ same type
ESRRB c.*1502A>T Uncertain significance ★★ same type
ESRRB c.*1534C>T Uncertain significance ★★ same type
ESRRB c.*1550C>A Uncertain significance ★★ same type
ESRRB c.*1559A>G 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-c-577-plus-2t-c (accessed [today's date]).

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