Is RGR p.Pro45Ser (c.133C>T) pathogenic?

RGR p.Pro45Ser (c.133C>T) is classified Uncertain significance in RGR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely benign (0.1062); Very rare (popmax 0.00446%, eas).

How common is RGR p.Pro45Ser (c.133C>T) in the general population?

RGR p.Pro45Ser (c.133C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about RGR p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

RGR p.Pro45Ser

c.133C>T · VCV3314068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.78	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 1.5	GERP 5.4, phastCons 0.002
Overall
CADD	20.9	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,212 alleles · very rare exomes 2/1,461,890 · genomes 0/152,322 · 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: RGR
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_001012720
Type: single nucleotide variant
Location: chr10:84247644 (GRCh38)
Structure: AlphaFold pLDDT 62.88

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

Similar variants

RGR p.Pro45= Conflicting classifications of pathogenicity ★ same residue
RGR p.Pro45Leu Uncertain significance ★ ⚠ same residue
RGR c.358+1G>A Uncertain significance ★★ same type
RGR p.Ala110Thr Uncertain significance ★★ ⚠ same type
RGR p.Ala186Thr Uncertain significance ★★ ⚠ same type
RGR p.Ala217Gly Uncertain significance ★★ ⚠ same type
RGR p.Ala234Thr Uncertain significance ★★ ⚠ same type
RGR p.Ala251Thr 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/rgr-p-pro45ser (accessed [today's date]).

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