Is PGR p.Pro708Ser (c.2122C>T) pathogenic?

PGR p.Pro708Ser (c.2122C>T) is classified Uncertain significance in PGR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: ambiguous (0.4966); Very rare (popmax 0.00134%, afr).

How common is PGR p.Pro708Ser (c.2122C>T) in the general population?

PGR p.Pro708Ser (c.2122C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PGR p.Pro708Ser (c.2122C>T)?

AlphaMissense predicts ambiguous (score 0.4966) — an in-silico prediction, not a clinical call.

PGR p.Pro708Ser

c.2122C>T · VCV3417469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.4966	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -10.35	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.7, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 24 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	24.3	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 0.00134% African / African-American · 1/74,890 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,874 alleles · very rare exomes 3/1,461,716 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,890
European (non-Finnish)	0.000254%	393,304

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.Pro708Ser
Coding: c.2122C>T
MANE Select: NM_000926
Type: single nucleotide variant
Location: chr11:101062537 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 57.66 · 21 PDB
Residue 708: the nr lbd domain; the 'af2; mediates transcriptional activation' region; an α-helix

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

Similar variants

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
PGR p.Gly435= Likely 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-pro708ser (accessed [today's date]).

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