# NM_001164688.2(RD3):c.57G>A (p.Arg19=)

https://sugi.bio/variant/rd3-p-arg19

## Summary

**RD3 p.Arg19= (c.57G>A)** is classified **Likely benign** in RD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). Very rare (popmax 0.00988%, sas); Associated with Leber congenital amaurosis 12.

**At a glance:** Likely benign · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 0.00988%, sas)

## For patients & families {#patients}

This is a change in the RD3 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Leber congenital amaurosis 12.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | RD3 is a diagnostic-grade gene on 1 Genomics England panel |

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

- Severely reduced visual acuity — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Abnormality of the optic disc — Very frequent (99-80%)
- Abnormal electroretinogram — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Hypermetropia — Frequent (79-30%)
- Keratoconus — Frequent (79-30%)
- Photophobia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010489/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RD3](https://sugi.bio/atlas/gene/RD3/) |
| Protein change (HGVS p.) | p.Arg19= |
| Coding change (HGVS c.) | c.57G>A |
| MANE Select transcript | [NM_001164688](https://www.ncbi.nlm.nih.gov/nuccore/NM_001164688) |
| Variant type | single nucleotide variant |
| Location | chr1:211481359-211481359 (GRCh38) |
| ClinVar | [VCV4754583](https://www.ncbi.nlm.nih.gov/clinvar/variation/4754583/) |

**All HGVS expressions:** `NC_000001.10:g.211654701C>T`, `NC_000001.11:g.211481359C>T`, `NG_013042.1:g.16559G>A`, `NM_001164688.2:c.57G>A`, `NM_183059.3:c.57G>A`

## 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 **acceptor loss** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.599, GERP 2, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 8.691**. 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 **0.27**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00988%** (sas) · FAF95 0.00514% · FAF99 0.00375% · 9/91,074 in the highest group · 18/1,613,984 alleles overall — very rare (popmax 0.00988%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00988% | 10,119 |
| East Asian | 0.00446% | 22,439 |
| European (non-Finnish) | 0.000593% | 168,578 |

*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}

**RD3** population constraint: LOEUF 1.116, pLI 0.0021536, missense-Z -0.001529. *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):

- **RD3-related retinopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.99, 52% of residues very-high.

**1 experimental structure(s)** (PDB): [6DRF](https://www.rcsb.org/structure/6DRF).

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-23.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-17 |

## Associated conditions {#conditions}

[Leber congenital amaurosis 12](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-12/).

**Reported phenotype names (ClinVar):** Leber congenital amaurosis 12, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related RD3 variant pages (same residue, condition, or type): [RD3 p.Arg19Trp](/variant/rd3-p-arg19trp), [RD3 c.296+1G>T](/variant/rd3-c-296-plus-1g-t), [RD3 p.Arg38Ter](/variant/rd3-p-arg38ter), [RD3 p.Tyr60Ter](/variant/rd3-p-tyr60ter), [RD3 c.-572G>A](/variant/rd3-c-minus-572g-a), [RD3 c.*1277G>A](/variant/rd3-c-star-1277g-a), [RD3 p.Ala135Val](/variant/rd3-p-ala135val), [RD3 p.Arg15Trp](/variant/rd3-p-arg15trp).

### 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 4754583). 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.*