Is PGR p.Ala254Pro (c.760G>C) pathogenic?

PGR p.Ala254Pro (c.760G>C) is classified Uncertain significance in PGR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0861); Very rare (popmax 8.5e-05%, nfe).

How common is PGR p.Ala254Pro (c.760G>C) in the general population?

PGR p.Ala254Pro (c.760G>C) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about PGR p.Ala254Pro (c.760G>C)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

PGR p.Ala254Pro

c.760G>C · rs1241953281 · VCV2237229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.68
Regional constraint	o/e 1.14	unconstrained · MANE · 2,957 bp · p 0.00013 · regional, not allelic
Overall
CADD	10.52	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,510 alleles

Overall 6.27e-05% 1/1,594,220 alleles · very rare exomes 0/1,442,032 · genomes 1/152,188 · 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: PGR
Protein: p.Ala254Pro
Coding: c.760G>C
MANE Select: NM_000926
dbSNP: rs1241953281
Type: single nucleotide variant
Location: chr11:101128311 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 57.66 · 21 PDB
Residue 254: the 'modulating, pro-rich' region; the 'mediates transcriptional transrepression (in isoform a)' region

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

Similar variants

PGR p.Ala254Thr Uncertain significance ★ ⚠ same residue
PGR p.Arg187= Benign ★★ same type
PGR p.Arg623= Benign ★★ same type
PGR p.Cys347Ser Benign ★★ same type
PGR p.Gln536Pro Benign ★★ same type
PGR p.Gln75Lys Likely benign ★★ same type
PGR p.Gln868= Benign ★★ same type
PGR p.Gly263= Benign ★★ 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/pgr-p-ala254pro (accessed [today's date]).

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