Is RGR p.Ser243Phe (c.728C>T) pathogenic?

RGR p.Ser243Phe (c.728C>T) is classified Uncertain significance in RGR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.3558); Very rare (popmax 0.000678%, nfe).

How common is RGR p.Ser243Phe (c.728C>T) in the general population?

RGR p.Ser243Phe (c.728C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about RGR p.Ser243Phe (c.728C>T)?

AlphaMissense predicts ambiguous (score 0.3558) — an in-silico prediction, not a clinical call.

RGR p.Ser243Phe

c.728C>T · rs144262093 · VCV1021577

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3558	ambiguous
REVEL	0.369	indeterminate
SaProt	LLR -14.11	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 6.6, phastCons 0.95
Overall
CADD	25.7	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 0.000678% European (non-Finnish) · 8/1,179,870 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,796 alleles · very rare exomes 5/1,461,622 · genomes 3/152,174 · 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.Ser243Phe
Coding: c.728C>T
MANE Select: NM_001012720
dbSNP: rs144262093
Type: single nucleotide variant
Location: chr10:84257990 (GRCh38)
Structure: AlphaFold pLDDT 62.88
Residue 243: the ras-gef domain

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

Similar variants

RGR p.Ser243= 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-ser243phe (accessed [today's date]).

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