# NM_014425.5(INVS):c.309C>T (p.Arg103=)

https://sugi.bio/variant/invs-p-arg103

## Summary

**INVS p.Arg103= (c.309C>T)** is classified **Likely benign** in INVS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). Very rare (popmax 8.48e-05%, nfe); Associated with nephronophthisis.

**At a glance:** Likely benign · review: Single submitter · rsID rs1831309614 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the INVS gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to nephronophthisis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | INVS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [INVS](https://sugi.bio/atlas/gene/INVS/) |
| Protein change (HGVS p.) | p.Arg103= |
| Coding change (HGVS c.) | c.309C>T |
| MANE Select transcript | [NM_014425](https://www.ncbi.nlm.nih.gov/nuccore/NM_014425) |
| dbSNP | [rs1831309614](https://www.ncbi.nlm.nih.gov/snp/rs1831309614/) |
| Variant type | single nucleotide variant |
| Location | chr9:100226097-100226097 (GRCh38) |
| ClinVar | [VCV2962617](https://www.ncbi.nlm.nih.gov/clinvar/variation/2962617/) |

**All HGVS expressions:** `NC_000009.11:g.102988379C>T`, `NC_000009.12:g.100226097C>T`, `NG_008316.1:g.131869C>T`, `NM_001318381.2:c.21C>T`, `NM_001318382.2:c.-681C>T`, `NM_014425.5:c.309C>T`, `NR_051962.1:n.618C>T`, `NR_134606.2:n.507C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.879, GERP -4.21 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.481**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,774 in the highest group · 1/1,613,630 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**INVS** population constraint: LOEUF 0.941, pLI 1.7464e-21, missense-Z 2.0948. *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):

- **nephronophthisis 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.76, 49% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-20 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Nephronophthisis, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related INVS variant pages (same residue, condition, or type): [INVS p.Arg103Cys](/variant/invs-p-arg103cys), [INVS p.Arg103Leu](/variant/invs-p-arg103leu), [INVS c.107-1G>A](/variant/invs-c-107-minus-1g-a), [INVS c.1078+1G>A](/variant/invs-c-1078-plus-1g-a), [INVS c.1464+1G>T](/variant/invs-c-1464-plus-1g-t), [INVS c.2068+2T>C](/variant/invs-c-2068-plus-2t-c), [INVS c.2069-1G>T](/variant/invs-c-2069-minus-1g-t), [INVS c.2786+1G>A](/variant/invs-c-2786-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2962617). 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.*