# NM_032119.4(ADGRV1):c.7576A>G (p.Ile2526Val)

https://sugi.bio/variant/adgrv1-p-ile2526val

## Summary

**ADGRV1 p.Ile2526Val (c.7576A>G)** is classified **Benign** in ADGRV1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0846); Common (popmax 6.79%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 2C.

**At a glance:** Benign · review: Multiple submitters · rsID rs75191159 · 10 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 6.79%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ADGRV1 gene that is classified as benign — not considered disease-causing, submitted by 10 submitters, and is linked to Usher syndrome type 2C.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008497/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADGRV1](https://sugi.bio/atlas/gene/ADGRV1/) |
| Protein change (HGVS p.) | p.Ile2526Val |
| Coding change (HGVS c.) | c.7576A>G |
| MANE Select transcript | [NM_032119](https://www.ncbi.nlm.nih.gov/nuccore/NM_032119) |
| dbSNP | [rs75191159](https://www.ncbi.nlm.nih.gov/snp/rs75191159/) |
| Variant type | single nucleotide variant |
| Location | chr5:90694332-90694332 (GRCh38) |
| ClinVar | [VCV46376](https://www.ncbi.nlm.nih.gov/clinvar/variation/46376/) |

**All HGVS expressions:** `LRG_1095:g.169989A>G`, `LRG_1095t1:c.7576A>G`, `NC_000005.10:g.90694332A>G`, `NC_000005.9:g.89990149A>G`, `NG_007083.2:g.169989A>G`, `NM_032119.4:c.7576A>G`, `NR_003149.2:n.7592A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.79%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0846)
- REVEL 0.06 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -0.714, GERP -5.5 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 0.034**. 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.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (90,657,953–90,789,789), spanning 131,836 bp. Chi-square p 0.0071. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **6.79%** (afr) · FAF95 6.63% · FAF99 6.57% · 5,094/75,036 in the highest group · 5,912/1,613,950 alleles overall — common (popmax 6.79%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 6.79% | 15 |
| Remaining individuals (not grpmax-eligible) | 0.44% | 227 |
| Admixed American | 0.432% | 232 |
| Middle Eastern | 0.165% | 606 |
| European (non-Finnish) | 0.0219% | 4,573 |
| South Asian | 0.0132% | 7,590 |
| East Asian | 0.00668% | 14,961 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,022 |

*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}

**ADGRV1** population constraint: LOEUF 0.637, pLI 6.4034e-36, missense-Z 2.3256. *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):

- **nonsyndromic genetic hearing loss** — Disputed (AR)
- **Usher syndrome type 2** — Definitive (AR)

## Protein context {#protein}

Residue **2526** lies in the calx-beta 17 domain.

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

*Describes the biological roles of ADGRV1 (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:** ADGRV1's established molecular role includes calcium ion binding. p.Ile2526Val falls in the calx-beta 17 domain.


### Pathways affected {#pathways}

ADGRV1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | electronic |

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

**Molecular function:** calcium ion binding.

**Biological process:** sensory perception of sound, photoreceptor cell maintenance, maintenance of animal organ identity, nervous system process, sensory perception of light stimulus.

## Clinical significance {#significance}

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

**Submitter consensus:** conflicting (8 Benign, 2 Likely benign).

**Submission history:** 10 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-12-14 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | no assertion criteria provided | clinical testing | 2009-11-24 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2020-10-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-06-06 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2023-10-16 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[Usher syndrome type 2C](https://sugi.bio/atlas/disease/usher-syndrome-type-2c/).

**Reported phenotype names (ClinVar):** Usher syndrome type 2C, not specified, not provided, AllHighlyPenetrant, none provided, Usher syndrome, type 2B, USHER SYNDROME, TYPE IIC.

## Similar variants {#similar}

Related ADGRV1 variant pages (same residue, condition, or type): [ADGRV1 p.Ile2526Leu](/variant/adgrv1-p-ile2526leu), [ADGRV1 p.Ile2526Thr](/variant/adgrv1-p-ile2526thr), [ADGRV1 p.Ile2526=](/variant/adgrv1-p-ile2526), [ADGRV1 c.10974+1G>A](/variant/adgrv1-c-10974-plus-1g-a), [ADGRV1 c.11757+2T>C](/variant/adgrv1-c-11757-plus-2t-c), [ADGRV1 c.1239-1G>T](/variant/adgrv1-c-1239-minus-1g-t), [ADGRV1 c.13232-1G>A](/variant/adgrv1-c-13232-minus-1g-a), [ADGRV1 c.14972+1G>T](/variant/adgrv1-c-14972-plus-1g-t).

### 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 46376). 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.*