Is RGR p.Pro226Ser (c.676C>T) pathogenic?

RGR p.Pro226Ser (c.676C>T) is classified Uncertain significance in RGR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-25). AlphaMissense: ambiguous (0.5062); Very rare (popmax 0.000339%, nfe).

How common is RGR p.Pro226Ser (c.676C>T) in the general population?

RGR p.Pro226Ser (c.676C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about RGR p.Pro226Ser (c.676C>T)?

AlphaMissense predicts ambiguous (score 0.5062) — an in-silico prediction, not a clinical call.

RGR p.Pro226Ser

c.676C>T · rs1254582525 · VCV1460566

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5062	ambiguous · top 9% in RGR
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -12.24	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 6.6, phastCons 1
Overall
CADD	26.1	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 0.000339% European (non-Finnish) · 4/1,180,056 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,100 alleles · very rare exomes 3/1,461,884 · genomes 1/152,216 · 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.Pro226Ser
Coding: c.676C>T
MANE Select: NM_001012720
dbSNP: rs1254582525
Type: single nucleotide variant
Location: chr10:84257938 (GRCh38)
Structure: AlphaFold pLDDT 62.88
Residue 226: the ras-gef domain

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

Similar variants

RGR p.Pro226= Likely benign ★ 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
RGR p.Ala251Val 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-pro226ser (accessed [today's date]).

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