Is RFX3 p.Arg73Pro (c.218G>C) pathogenic?

RFX3 p.Arg73Pro (c.218G>C) is classified Uncertain significance in RFX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.8635); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RFX3 p.Arg73Pro (c.218G>C)?

RFX3 p.Arg73Pro (c.218G>C) is associated with Inborn genetic diseases (ClinVar).

How common is RFX3 p.Arg73Pro (c.218G>C) in the general population?

RFX3 p.Arg73Pro (c.218G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RFX3 p.Arg73Pro (c.218G>C)?

AlphaMissense predicts likely pathogenic (score 0.8635) — an in-silico prediction, not a clinical call.

RFX3 p.Arg73Pro

c.218G>C · VCV3945020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8635 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8635	likely pathogenic
REVEL	0.271	benign-leaning
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 65 kb · p 0.38 · regional, not allelic
Overall
CADD	27.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RFX3
Protein: p.Arg73Pro
Coding: c.218G>C
MANE Select: NM_001282116
Type: single nucleotide variant
Location: chr9:3330515 (GRCh38)
Gene constraint: LOEUF 0.212 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 67.90

Full RFX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RFX3 p.Arg73Leu Uncertain significance ⚠ same residue
RFX3 p.Met558Val Uncertain significance ★★ ⚠ same condition
RFX3 p.Ser389Cys Uncertain significance ★★ ⚠ same condition
RFX3 p.Arg255His Likely pathogenic ★ same condition
RFX3 p.Gln596Ter Pathogenic ★ same condition
RFX3 p.Ala162Val Uncertain significance ★ ⚠ same condition
RFX3 p.Ala222Asp Uncertain significance ★ ⚠ same condition
RFX3 p.Ala326Gly Uncertain significance ★ ⚠ same condition

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/rfx3-p-arg73pro (accessed [today's date]).

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