# NM_174878.3(CLRN1):c.6A>C (p.Pro2=)

https://sugi.bio/variant/clrn1-p-pro2

## Summary

**CLRN1 p.Pro2= (c.6A>C)** is classified **Benign** in CLRN1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 3.

**At a glance:** Benign · review: Multiple submitters · rsID rs111033422 · 8 submitters · 2 linked conditions · common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CLRN1 gene that is classified as benign — not considered disease-causing, submitted by 8 submitters, and is linked to Usher syndrome type 3.

*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) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CLRN1 is a diagnostic-grade gene on 3 Genomics England panels |

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

- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Progressive visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Visual field defect — Very frequent (99-80%)
- Abnormal vestibular function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005442/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLRN1](https://sugi.bio/atlas/gene/CLRN1/) |
| Protein change (HGVS p.) | p.Pro2= |
| Coding change (HGVS c.) | c.6A>C |
| MANE Select transcript | [NM_174878](https://www.ncbi.nlm.nih.gov/nuccore/NM_174878) |
| dbSNP | [rs111033422](https://www.ncbi.nlm.nih.gov/snp/rs111033422/) |
| Variant type | single nucleotide variant |
| Location | chr3:150972703-150972703 (GRCh38) |
| ClinVar | [VCV48148](https://www.ncbi.nlm.nih.gov/clinvar/variation/48148/) |

**All HGVS expressions:** `LRG_700:g.5297A>C`, `LRG_700t1:c.6A>C`, `NC_000003.11:g.150690490T>G`, `NC_000003.12:g.150972703T>G`, `NG_009168.1:g.5297A>C`, `NM_001195794.1:c.6A>C`, `NM_001256819.2:c.6A>C`, `NM_174878.3:c.6A>C`, `NR_024066.2:n.26T>G`, `NR_046380.3:n.25A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 0.089, GERP 0.5, phastCons 0.966 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.493**. 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: **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 **12.6%** (afr) · FAF95 12.4% · FAF99 12.3% · 9,449/75,024 in the highest group · 13,887/1,614,180 alleles overall — common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 12.6% | 8 |
| South Asian | 2.94% | 34 |
| Remaining individuals (not grpmax-eligible) | 1.16% | 86 |
| Middle Eastern | 1.12% | 89 |
| Admixed American | 0.741% | 135 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.149% | 673 |
| European (non-Finnish) | 0.0399% | 2,505 |
| East Asian | 0.00668% | 14,963 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,018 |

*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}

**CLRN1** population constraint: LOEUF 1.168, pLI 8.5957e-05, missense-Z -0.36895; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **Usher syndrome type 3** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.74, 77% of residues very-high.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 1 not provided).

**Submission history:** 8 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| NEI Ophthalmic Genomics Laboratory, National Institutes of Health | not provided | no classification provided | not provided |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-04-30 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2011-06-09 |
| Counsyl | Benign | no assertion criteria provided | clinical testing | 2018-01-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[Usher syndrome type 3](https://sugi.bio/atlas/disease/usher-syndrome-type-3/), [Usher syndrome type 3A](https://sugi.bio/atlas/disease/usher-syndrome-type-3a/).

**Reported phenotype names (ClinVar):** Usher syndrome type 3, not specified, not provided, Usher syndrome type 3A, USHER SYNDROME, TYPE IIIA, AllHighlyPenetrant, none provided, Usher Syndrome, Type III.

## Similar variants {#similar}

Related CLRN1 variant pages (same residue, condition, or type): [CLRN1 c.253+1G>A](/variant/clrn1-c-253-plus-1g-a), [CLRN1 c.253+6T>C](/variant/clrn1-c-253-plus-6t-c), [CLRN1 c.254-2A>G](/variant/clrn1-c-254-minus-2a-g), [CLRN1 c.433+1G>A](/variant/clrn1-c-433-plus-1g-a), [CLRN1 c.433+1G>T](/variant/clrn1-c-433-plus-1g-t), [CLRN1 p.Ala123Asp](/variant/clrn1-p-ala123asp), [CLRN1 p.Arg207Ter](/variant/clrn1-p-arg207ter), [CLRN1 p.Asn202Lys](/variant/clrn1-p-asn202lys).

### 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 48148). 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.*