Is ESRRB p.Ala344Val (c.1031C>T) pathogenic?

ESRRB p.Ala344Val (c.1031C>T) is classified Uncertain significance in ESRRB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-23). Very rare (popmax 0.00116%, sas).

How common is ESRRB p.Ala344Val (c.1031C>T) in the general population?

ESRRB p.Ala344Val (c.1031C>T) is very rare (popmax 0.00116%, sas) (gnomAD).

ESRRB p.Ala344Val

c.1031C>T · rs766812921 · VCV2075211

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.585	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 122 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00116% South Asian · 1/86,438 alleles

Overall 0.000568% 9/1,584,150 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0114%	8,792
South Asiangrpmax	0.00116%	86,438
European (non-Finnish)	8.57e-05%	1,166,302

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala344Val
Coding: c.1031C>T
MANE Select: NM_001379180
dbSNP: rs766812921
Type: single nucleotide variant
Location: chr14:76491627 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 3 PDB
Residue 344: 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

Similar variants

ESRRB p.Ala344= 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-ala344val (accessed [today's date]).

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