# NM_006912.6(RIT1):c.21A>G (p.Pro7=)

https://sugi.bio/variant/rit1-p-pro7

## Summary

**RIT1 p.Pro7= (c.21A>G)** is classified **Uncertain significance** in RIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-01). Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RIT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RIT1](https://sugi.bio/atlas/gene/RIT1/) |
| Protein change (HGVS p.) | p.Pro7= |
| Coding change (HGVS c.) | c.21A>G |
| MANE Select transcript | [NM_006912](https://www.ncbi.nlm.nih.gov/nuccore/NM_006912) |
| Variant type | single nucleotide variant |
| Location | chr1:155910741-155910741 (GRCh38) |
| ClinVar | [VCV4278842](https://www.ncbi.nlm.nih.gov/clinvar/variation/4278842/) |

**All HGVS expressions:** `LRG_1372:g.5662A>G`, `LRG_1372t1:c.21A>G`, `NC_000001.10:g.155880532T>C`, `NC_000001.11:g.155910741T>C`, `NG_033885.1:g.5662A>G`, `NM_001256820.2:c.-2-235A>G`, `NM_001256821.2:c.72A>G`, `NM_006912.6:c.21A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.65) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -4.41, GERP -2.98 — fast-evolving / accelerated position
- CADD: **PHRED 14.74**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.14**, acceptor gain **0.00**, donor gain **0.65**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.65**.
- Pangolin: Δ**0.42** (gain), gain 0.42 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RIT1** population constraint: LOEUF 0.523, pLI 0.96123, missense-Z 1.5009; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Noonan syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.78, 73% of residues very-high.

**3 experimental structure(s)** (PDB): [4KLZ](https://www.rcsb.org/structure/4KLZ), [9MEY](https://www.rcsb.org/structure/9MEY), [9MF1](https://www.rcsb.org/structure/9MF1).

## What this gene does {#gene-function}

*Describes the biological roles of RIT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RIT1's established molecular role includes GTPase activity.


### Pathways affected {#pathways}

RIT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signalling to p38 via RIT and RIN](https://reactome.org/content/detail/R-HSA-187706) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activity, GTP binding.

**Biological process:** Ras protein signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RIT1 variant pages (same residue, condition, or type): [RIT1 p.Met90Val](/variant/rit1-p-met90val), [RIT1 p.Arg123Cys](/variant/rit1-p-arg123cys), [RIT1 p.Gly78Glu](/variant/rit1-p-gly78glu), [RIT1 p.Ala57Gly](/variant/rit1-p-ala57gly), [RIT1 p.Ala77Gly](/variant/rit1-p-ala77gly), [RIT1 p.Ala77Pro](/variant/rit1-p-ala77pro), [RIT1 p.Ala77Ser](/variant/rit1-p-ala77ser), [RIT1 p.Ala77Thr](/variant/rit1-p-ala77thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4278842). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*