Is PGR p.Cys347Ser (c.1040G>C) pathogenic?

PGR p.Cys347Ser (c.1040G>C) is classified Benign in PGR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0493); Common (popmax 9.85%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PGR p.Cys347Ser (c.1040G>C)?

AlphaMissense predicts likely benign (score 0.0493) — an in-silico prediction, not a clinical call.

PGR p.Cys347Ser

Q: How common is PGR p.Cys347Ser (c.1040G>C) in the general population?

PGR p.Cys347Ser (c.1040G>C) is common (popmax 9.85%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1040G>C · rs11571147 · VCV768473

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0493 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.85%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0493	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -4.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 2,957 bp · p 0.00013 · regional, not allelic
Overall
CADD	15.4	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 9.85% African / African-American · 7,389/75,020 alleles

Filtering AF 9.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.58%

Overall 0.512% 8,239/1,607,940 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.85%	10
Remaining individualsnot grpmax-eligible	0.629%	159
Admixed American	0.443%	226
Middle Eastern	0.396%	252
South Asian	0.022%	4,553
European (non-Finnish)	0.0125%	8,026

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.Cys347Ser
Coding: c.1040G>C
MANE Select: NM_000926
dbSNP: rs11571147
Type: single nucleotide variant
Location: chr11:101128031 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 57.66 · 21 PDB
Residue 347: the 'disordered' region; a UniProt-annotated variant site (in); the 'modulating, pro-rich' region

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.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
PGR p.Gly661= 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-cys347ser (accessed [today's date]).

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