Is RIT1 p.Pro199Ser (c.595C>T) pathogenic?

RIT1 p.Pro199Ser (c.595C>T) is classified Uncertain significance in RIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.1094); Very rare (popmax 0.000124%); Associated with Cardiovascular phenotype.

What condition is associated with RIT1 p.Pro199Ser (c.595C>T)?

RIT1 p.Pro199Ser (c.595C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is RIT1 p.Pro199Ser (c.595C>T) in the general population?

RIT1 p.Pro199Ser (c.595C>T) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about RIT1 p.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

RIT1 p.Pro199Ser

c.595C>T · VCV3894981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 199 bp · p 0.76 · regional, not allelic
Overall
CADD	21.4	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 0.000124%

Overall 0.000124% 2/1,614,046 alleles · very rare exomes 2/1,461,868 · genomes 0/152,178 · 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: RIT1
Protein: p.Pro199Ser
Coding: c.595C>T
MANE Select: NM_006912
Type: single nucleotide variant
Location: chr1:155900453 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 3 PDB
Residue 199: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIT1 p.Ala77Gly Pathogenic/Likely pathogenic ★★ same condition
RIT1 p.Lys23Gln Pathogenic/Likely pathogenic ★★ same condition
RIT1 p.Phe82Val Pathogenic ★★ same condition
RIT1 p.Ala151Val Uncertain significance ★★ ⚠ same condition
RIT1 p.Ala16Thr Uncertain significance ★★ ⚠ same condition
RIT1 p.Ala192Val Uncertain significance ★★ ⚠ same condition
RIT1 p.Arg105Cys Uncertain significance ★★ ⚠ same condition
RIT1 p.Arg120Gln 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/rit1-p-pro199ser (accessed [today's date]).

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