# NM_006262.4(PRPH):c.860A>G (p.Tyr287Cys)

https://sugi.bio/variant/prph-p-tyr287cys

## Summary

**PRPH p.Tyr287Cys (c.860A>G)** is classified **Uncertain significance** in PRPH (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.9775); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs372095080 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the PRPH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [PRPH](https://sugi.bio/atlas/gene/PRPH/) |
| Protein change (HGVS p.) | p.Tyr287Cys |
| Coding change (HGVS c.) | c.860A>G |
| MANE Select transcript | [NM_006262](https://www.ncbi.nlm.nih.gov/nuccore/NM_006262) |
| dbSNP | [rs372095080](https://www.ncbi.nlm.nih.gov/snp/rs372095080/) |
| Variant type | single nucleotide variant |
| Location | chr12:49297046-49297046 (GRCh38) |
| ClinVar | [VCV1050072](https://www.ncbi.nlm.nih.gov/clinvar/variation/1050072/) |

**All HGVS expressions:** `NC_000012.11:g.49690829A>G`, `NC_000012.12:g.49297046A>G`, `NG_008354.1:g.6921A>G`, `NM_006262.3:c.860A>G`, `NM_006262.4:c.860A>G`, `NR_120449.1:n.1157T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9775)
- REVEL 0.937 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.485 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.198, GERP 1.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in PRPH (of 2,755 modeled).
- CADD: **PHRED 32.0**. 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 0.91** across the covering region of the MANE Select transcript (49,295,201–49,298,350), spanning 3,149 bp. Chi-square p 0.024. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 3 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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 **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,902 in the highest group · 7/1,613,740 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00534% | 18,726 |
| Admixed American | 0.00167% | 59,996 |
| European (non-Finnish) | 0.000169% | 589,977 |

*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}

**PRPH** population constraint: LOEUF 1.161, pLI 1.7093e-15, missense-Z 0.80514. *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):

- **amyotrophic lateral sclerosis** — Limited (AD)

## Protein context {#protein}

Residue **287** lies in the if rod domain; the 'coil 2' region.

AlphaFold model confidence (whole protein): pLDDT 79.24, 56% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-29.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-29 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related PRPH variant pages (same residue, condition, or type): [PRPH p.Glu233Lys](/variant/prph-p-glu233lys), [PRPH p.Ile419Met](/variant/prph-p-ile419met), [PRPH p.Ala109Val](/variant/prph-p-ala109val), [PRPH p.Ala132Thr](/variant/prph-p-ala132thr), [PRPH p.Ala132Val](/variant/prph-p-ala132val), [PRPH p.Ala193Glu](/variant/prph-p-ala193glu), [PRPH p.Ala193Gly](/variant/prph-p-ala193gly), [PRPH p.Ala49Val](/variant/prph-p-ala49val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1050072). 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.*