Is ESRRG p.Pro43Ser (c.127C>T) pathogenic?

ESRRG p.Pro43Ser (c.127C>T) is classified Uncertain significance in ESRRG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely pathogenic (0.8709); Very rare (popmax 0.000424%, nfe).

How common is ESRRG p.Pro43Ser (c.127C>T) in the general population?

ESRRG p.Pro43Ser (c.127C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ESRRG p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely pathogenic (score 0.8709) — an in-silico prediction, not a clinical call.

ESRRG p.Pro43Ser

c.127C>T · VCV3276521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8709	likely pathogenic
REVEL	0.536	indeterminate
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 46 kb · p 0.84 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,026 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,148 alleles · very rare exomes 5/1,461,862 · genomes 0/152,286 · joint denominator

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: ESRRG
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_001438
Type: single nucleotide variant
Location: chr1:216677421 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.66 · 43 PDB
Residue 43: the 'disordered' region

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

Similar variants

ESRRG p.Arg184Cys Pathogenic/Likely pathogenic ★★ same type
ESRRG p.Cys164= Benign ★★ same type
ESRRG p.Cys170Arg Likely pathogenic ★ same type
ESRRG p.Cys180Tyr Likely pathogenic ★ same type
ESRRG p.Leu449Arg Likely pathogenic ★ same type
ESRRG p.Lys149Arg Likely pathogenic ★ same type
ESRRG p.Arg175Leu Uncertain significance ★ ⚠ same type
ESRRG p.Arg212Cys 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/esrrg-p-pro43ser (accessed [today's date]).

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