Is ESRRB p.Cys166Ter (c.498C>A) pathogenic?

ESRRB p.Cys166Ter (c.498C>A) is classified Pathogenic in ESRRB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Very rare (popmax 0.0022%, sas).

How common is ESRRB p.Cys166Ter (c.498C>A) in the general population?

ESRRB p.Cys166Ter (c.498C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

ESRRB p.Cys166Ter

c.498C>A · rs1064439 · VCV2137608

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5
Overall
CADD	36.0	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 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,706 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
Protein: p.Cys166Ter
Coding: c.498C>A
MANE Select: NM_001379180
dbSNP: rs1064439
Type: single nucleotide variant
Location: chr14:76462582 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 166: a DNA-binding region; an α-helix; the 'interaction with nanog' region

Full ESRRB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESRRB p.Cys166= Likely benign ★ same residue
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

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-cys166ter (accessed [today's date]).

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