Is RIT1 p.Pro15Ser (c.43C>T) pathogenic?

RIT1 p.Pro15Ser (c.43C>T) is classified Uncertain significance in RIT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). AlphaMissense: likely benign (0.0717); Absent from gnomAD v4.1; Associated with Noonan syndrome 8.

What condition is associated with RIT1 p.Pro15Ser (c.43C>T)?

RIT1 p.Pro15Ser (c.43C>T) is associated with Noonan syndrome 8 (ClinVar).

How common is RIT1 p.Pro15Ser (c.43C>T) in the general population?

RIT1 p.Pro15Ser (c.43C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RIT1 p.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

RIT1 p.Pro15Ser

c.43C>T · VCV3764106

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome 8

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -5.61	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 2.4	GERP 0.56, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 6,403 bp · p 0.0012 · regional, not allelic
Overall
CADD	15.11	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

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: RIT1
Protein: p.Pro15Ser
Coding: c.43C>T
MANE Select: NM_006912
Type: single nucleotide variant
Location: chr1:155910719 (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.Pro15= 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-pro15ser (accessed [today's date]).

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