Is RIT1 p.Ala77Ser (c.229G>T) pathogenic?

RIT1 p.Ala77Ser (c.229G>T) is classified Pathogenic/Likely pathogenic in RIT1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-03). AlphaMissense: likely pathogenic (0.8919); Very rare (popmax 8.5e-05%, nfe); Associated with RIT1-related disorder.

What condition is associated with RIT1 p.Ala77Ser (c.229G>T)?

RIT1 p.Ala77Ser (c.229G>T) is associated with RIT1-related disorder, Noonan syndrome 1, Noonan syndrome 8 (ClinVar).

How common is RIT1 p.Ala77Ser (c.229G>T) in the general population?

RIT1 p.Ala77Ser (c.229G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about RIT1 p.Ala77Ser (c.229G>T)?

AlphaMissense predicts likely pathogenic (score 0.8919) — an in-silico prediction, not a clinical call.

RIT1 p.Ala77Ser

c.229G>T · rs869025191 · VCV561621

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RIT1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8919	likely pathogenic ✓ concordant with ClinVar
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -11.61	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 6,403 bp · p 0.0012 · regional, not allelic
Overall
CADD	27.5	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 8.5e-05% European (non-Finnish) · 1/1,176,270 alleles

Overall 6.21e-05% 1/1,609,958 alleles · very rare exomes 1/1,457,670 · genomes 0/152,288 · 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.Ala77Ser
Coding: c.229G>T
MANE Select: NM_006912
dbSNP: rs869025191
Type: single nucleotide variant
Location: chr1:155904739 (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

RIT1-related disorder

Also linked: Noonan syndrome 1 Noonan syndrome 8

Similar variants

RIT1 p.Ala77Gly Pathogenic/Likely pathogenic ★★ same residue
RIT1 p.Ala77Pro Pathogenic/Likely pathogenic ★★ same residue
RIT1 p.Ala77Thr Pathogenic/Likely pathogenic ★★ same residue
RIT1 p.Ala77= Likely benign ★★ same residue
RIT1 p.Ala77_Gly78dup Uncertain significance ★ same residue
RIT1 p.Met90Val Pathogenic ★★★ ⚠ same condition
RIT1 p.Arg123Cys Uncertain significance ★★★ same condition
RIT1 p.Gly78Glu 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-ala77ser (accessed [today's date]).

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