Is RIT1 p.Phe82Ser (c.245T>C) pathogenic?

RIT1 p.Phe82Ser (c.245T>C) is classified Pathogenic in RIT1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 8.49e-05%, nfe); Associated with Noonan syndrome 1.

What condition is associated with RIT1 p.Phe82Ser (c.245T>C)?

RIT1 p.Phe82Ser (c.245T>C) is associated with Noonan syndrome 1 (ClinVar).

How common is RIT1 p.Phe82Ser (c.245T>C) in the general population?

RIT1 p.Phe82Ser (c.245T>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about RIT1 p.Phe82Ser (c.245T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

RIT1 p.Phe82Ser

c.245T>C · rs868208063 · VCV694696

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 1% in RIT1
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 6,403 bp · p 0.0012 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,466 alleles

Overall 6.2e-05% 1/1,612,302 alleles · very rare exomes 1/1,460,024 · genomes 0/152,278 · 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.Phe82Ser
Coding: c.245T>C
MANE Select: NM_006912
dbSNP: rs868208063
Type: single nucleotide variant
Location: chr1:155904495 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 3 PDB
Residue 82: a UniProt-annotated variant site (in ns8; results in increased elk1 transcriptional activation; abolishes interaction with lztr1); a UniProt-annotated variant site (found in patients with features of noonan syndrome; likely pathogenic)

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

Disease context

Noonan syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIT1 p.Phe82Cys Pathogenic ★★ same residue
RIT1 p.Phe82Ile Pathogenic ★★ same residue
RIT1 p.Phe82Leu Pathogenic/Likely pathogenic ★★ same residue
RIT1 p.Phe82Val Pathogenic ★★ same residue
RIT1 p.Phe82= Likely benign ★ same residue
RIT1 p.Ala57Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
RIT1 p.Ala77Ser Pathogenic/Likely pathogenic ★★ same condition
RIT1 p.Ala77Thr 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-phe82ser (accessed [today's date]).

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