# NM_014425.5(INVS):c.2685C>T (p.Pro895=)

https://sugi.bio/variant/invs-p-pro895

## Summary

**INVS p.Pro895= (c.2685C>T)** is classified **Likely benign** in INVS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0214%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs371932940 · 6 submitters · 3 linked conditions · ultra-rare (popmax 0.0214%, 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 6 submitters, and is linked to Inborn genetic diseases.

*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 | [INVS](https://sugi.bio/atlas/gene/INVS/) |
| Protein change (HGVS p.) | p.Pro895= |
| Coding change (HGVS c.) | c.2685C>T |
| MANE Select transcript | [NM_014425](https://www.ncbi.nlm.nih.gov/nuccore/NM_014425) |
| dbSNP | [rs371932940](https://www.ncbi.nlm.nih.gov/snp/rs371932940/) |
| Variant type | single nucleotide variant |
| Location | chr9:100292942-100292942 (GRCh38) |
| ClinVar | [VCV1623368](https://www.ncbi.nlm.nih.gov/clinvar/variation/1623368/) |

**All HGVS expressions:** `NC_000009.11:g.103055224C>T`, `NC_000009.12:g.100292942C>T`, `NG_008316.1:g.198714C>T`, `NM_001318381.2:c.2397C>T`, `NM_001318382.2:c.1707C>T`, `NM_014425.2:c.2685C>T`, `NM_014425.4:c.2685C>T`, `NM_014425.5:c.2685C>T`, `NR_134606.2:n.2834C>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 -3.678 — fast-evolving / accelerated position
- CADD: **PHRED 7.502**. 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, Δ0.75 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 **0.0214%** (nfe) · FAF95 0.0192% · FAF99 0.0183% · 252/1,179,168 in the highest group · 292/1,613,010 alleles overall — ultra-rare (popmax 0.0214%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0288% | 3,469 |
| European (non-Finnish) (grpmax) | 0.0214% | 4,679 |
| South Asian | 0.0165% | 6,071 |
| African / African-American | 0.00668% | 14,976 |
| East Asian | 0.00223% | 44,856 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,024 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (6/6 Likely benign).

**Submission history:** 6 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-14 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-12-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-30 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [nephronophthisis 2](https://sugi.bio/atlas/disease/nephronophthisis-2/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Nephronophthisis, not provided, Infantile nephronophthisis, INVS-related disorder, not specified, AllHighlyPenetrant, none provided, INVS-related condition, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related INVS variant pages (same residue, condition, or type): [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), [INVS c.2786+2T>C](/variant/invs-c-2786-plus-2t-c), [INVS c.615+1G>A](/variant/invs-c-615-plus-1g-a).

### 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 1623368). 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.*