# NM_001252024.2(TRPM1):c.1263G>A (p.Pro421=)

https://sugi.bio/variant/trpm1-p-pro421

## Summary

**TRPM1 p.Pro421= (c.1263G>A)** is classified **Conflicting classifications of pathogenicity** in TRPM1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-07-05). Very rare (popmax 0.00446%, eas); Associated with TRPM1-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs768701595 · 7 submitters · 4 linked conditions · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the TRPM1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to TRPM1-related disorder.

*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 | [TRPM1](https://sugi.bio/atlas/gene/TRPM1/) |
| Protein change (HGVS p.) | p.Pro421= |
| Coding change (HGVS c.) | c.1263G>A |
| MANE Select transcript | [NM_001252024](https://www.ncbi.nlm.nih.gov/nuccore/NM_001252024) |
| dbSNP | [rs768701595](https://www.ncbi.nlm.nih.gov/snp/rs768701595/) |
| Variant type | single nucleotide variant |
| Location | chr15:31060544-31060544 (GRCh38) |
| ClinVar | [VCV225502](https://www.ncbi.nlm.nih.gov/clinvar/variation/225502/) |

**All HGVS expressions:** `NC_000015.10:g.31060544C>T`, `NC_000015.9:g.31352747C>T`, `NG_016453.2:g.105730G>A`, `NM_001252020.2:c.1314G>A`, `NM_001252024.2:c.1263G>A`, `NM_002420.6:c.1197G>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 **donor loss** (Δ 0.46) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.218, GERP 2.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.1**. 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 **0.00**, donor loss **0.46**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- 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.*
- Pangolin: Δ**0.33** (loss), gain 0.02 / loss 0.33. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,884 in the highest group · 13/1,613,684 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,442 |
| Admixed American | 0.00333% | 30,012 |
| European (non-Finnish) | 0.000763% | 131,065 |

*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}

**TRPM1** population constraint: LOEUF 0.839, pLI 7.0919e-27, missense-Z 1.3804; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **TRPM1-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **421** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 66.74, 17% of residues very-high.

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

*Describes the biological roles of TRPM1 (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:** TRPM1's established molecular role includes calcium channel activity. p.Pro421= falls in the disordered region.


### Pathways affected {#pathways}

TRPM1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | curated |
| [TRP channels](https://reactome.org/content/detail/R-HSA-3295583) | curated |

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

**Molecular function:** calcium channel activity, monoatomic cation transmembrane transporter activity.

**Biological process:** G protein-coupled glutamate receptor signaling pathway, visual perception, cellular response to light stimulus, monoatomic cation transmembrane transport, calcium ion import across plasma membrane.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-07-05.

**Submitter consensus:** conflicting (3 Uncertain significance, 3 Likely pathogenic, 2 Pathogenic).

**Submission history:** 8 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Uncertain significance | criteria provided, single submitter | reference population | 2016-03-18 |
| Sharon lab, Hadassah-Hebrew University Medical Center | Likely pathogenic | no assertion criteria provided | research | 2019-06-23 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-02 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Dubai Health Genomic Medicine Center, Dubai Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-11-02 |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-11 |
| Dubai Health Genomic Medicine Center, Dubai Health | Likely pathogenic | criteria provided, single submitter | research | 2024-10-04 |
| Department of Molecular Genetics, Istishari Arab Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2026-07-05 |

## Associated conditions {#conditions}

[TRPM1-related disorder](https://sugi.bio/atlas/disease/trpm1-related-disorder/), [night blindness](https://sugi.bio/atlas/disease/night-blindness/), [congenital stationary night blindness 1C](https://sugi.bio/atlas/disease/congenital-stationary-night-blindness-1c/), [congenital stationary night blindness](https://sugi.bio/atlas/disease/congenital-stationary-night-blindness/).

**Reported phenotype names (ClinVar):** TRPM1-related disorder, Congenital stationary night blindness 1C, Congenital stationary night blindness, Night blindness, TRPM1-related condition, Nyctalopia, Early-onset non-progressive night blindness, Night blindness, congenital stationary (complete), 1C, autosomal recessive.

## Similar variants {#similar}

Related TRPM1 variant pages (same residue, condition, or type): [TRPM1 p.Pro421Thr](/variant/trpm1-p-pro421thr), [TRPM1 p.Pro421Leu](/variant/trpm1-p-pro421leu), [TRPM1 c.1089+1G>A](/variant/trpm1-c-1089-plus-1g-a), [TRPM1 c.2316+1G>A](/variant/trpm1-c-2316-plus-1g-a), [TRPM1 c.2317-1G>C](/variant/trpm1-c-2317-minus-1g-c), [TRPM1 c.2440-2A>G](/variant/trpm1-c-2440-minus-2a-g), [TRPM1 c.3127+1G>A](/variant/trpm1-c-3127-plus-1g-a), [TRPM1 c.3148+1G>A](/variant/trpm1-c-3148-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 225502). 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.*