Is RIT1 p.Ser217= (c.651A>G) pathogenic?

RIT1 p.Ser217= (c.651A>G) is classified Likely benign in RIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-10). Very rare (popmax 0.0022%, sas); Associated with Noonan syndrome 8.

What condition is associated with RIT1 p.Ser217= (c.651A>G)?

RIT1 p.Ser217= (c.651A>G) is associated with Noonan syndrome 8 (ClinVar).

How common is RIT1 p.Ser217= (c.651A>G) in the general population?

RIT1 p.Ser217= (c.651A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

RIT1 p.Ser217=

c.651A>G · rs762892205 · VCV2769679

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Noonan syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -7.2	GERP -3.9
Overall
CADD	0.729	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,062 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,034 alleles · very rare exomes 6/1,460,692 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,531
European (non-Finnish)	0.000339%	294,764

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.Ser217=
Coding: c.651A>G
MANE Select: NM_006912
dbSNP: rs762892205
Type: single nucleotide variant
Location: chr1:155900397 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 3 PDB
Residue 217: the 'disordered' region

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.Ser217Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
RIT1 p.Ser217fs Uncertain significance ★ same residue
RIT1 p.Ser217Ala Uncertain significance ★ ⚠ 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

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-ser217 (accessed [today's date]).

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