Is RIT1 p.Arg6Pro (c.17G>C) pathogenic?

RIT1 p.Arg6Pro (c.17G>C) is classified Uncertain significance in RIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-11). AlphaMissense: likely benign (0.1108); Very rare (popmax 0.00133%, afr); Associated with Noonan syndrome 8.

What condition is associated with RIT1 p.Arg6Pro (c.17G>C)?

RIT1 p.Arg6Pro (c.17G>C) is associated with Noonan syndrome 8 (ClinVar).

How common is RIT1 p.Arg6Pro (c.17G>C) in the general population?

RIT1 p.Arg6Pro (c.17G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RIT1 p.Arg6Pro (c.17G>C)?

AlphaMissense predicts likely benign (score 0.1108) — an in-silico prediction, not a clinical call.

RIT1 p.Arg6Pro

c.17G>C · rs1255067143 · VCV1903746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome 8

Computational evidence

Protein change
AlphaMissense	0.1108	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -5.92	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 7.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 6,403 bp · p 0.0012 · regional, not allelic
Overall
CADD	22.9	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 0.00133% African / African-American · 1/74,934 alleles

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

Overall 0.00031% 5/1,614,116 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,934
European (non-Finnish)	0.000339%	295,012

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: RIT1
Protein: p.Arg6Pro
Coding: c.17G>C
MANE Select: NM_006912
dbSNP: rs1255067143
Type: single nucleotide variant
Location: chr1:155910745 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 3 PDB

Full RIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Noonan syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIT1 p.Arg6= Likely benign ★★ same residue
RIT1 p.Met90Val Pathogenic ★★★ ⚠ same condition
RIT1 p.Arg123Cys Uncertain significance ★★★ same condition
RIT1 p.Gly78Glu Uncertain significance ★★★ ⚠ same condition
RIT1 p.Ala57Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
RIT1 p.Ala77Gly Pathogenic/Likely pathogenic ★★ same condition
RIT1 p.Ala77Pro Pathogenic/Likely pathogenic ★★ same condition
RIT1 p.Ala77Ser Pathogenic/Likely pathogenic ★★ 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/rit1-p-arg6pro (accessed [today's date]).

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