# NM_003322.6(TULP1):c.855dup (p.Val286fs)

https://sugi.bio/variant/tulp1-p-val286fs

## Summary

**TULP1 p.Val286fs (c.855dup)** is classified **Pathogenic/Likely pathogenic** in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-18). Very rare (popmax 0.0022%, sas); Associated with retinitis pigmentosa.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1554125752 · 2 submitters · 2 linked conditions · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the TULP1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to retinitis pigmentosa.

*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, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TULP1 is a diagnostic-grade gene on 1 Genomics England panel |

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

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TULP1](https://sugi.bio/atlas/gene/TULP1/) |
| Protein change (HGVS p.) | p.Val286fs |
| Coding change (HGVS c.) | c.855dup |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs1554125752](https://www.ncbi.nlm.nih.gov/snp/rs1554125752/) |
| Variant type | Duplication |
| Location | chr6:35506146-35506147 (GRCh38) |
| ClinVar | [VCV505327](https://www.ncbi.nlm.nih.gov/clinvar/variation/505327/) |

**All HGVS expressions:** `NC_000006.11:g.35473929dup`, `NC_000006.12:g.35506152dup`, `NG_009077.1:g.11724dup`, `NM_001289395.2:c.696dup`, `NM_003322.6:c.855dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.126, GERP -1.53 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.019, pLI 2.9584e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000429% · FAF99 0.000313% · 2/91,056 in the highest group · 13/1,613,504 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,528 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,480 |
| European (non-Finnish) | 0.000848% | 117,988 |

*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}

**TULP1** population constraint: LOEUF 1.019, pLI 2.9584e-14, missense-Z -0.39346. *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):

- **Leber congenital amaurosis 15** — Definitive (AR)

## Protein context {#protein}

Residue **286** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 66.10, 32% of residues very-high.

**2 experimental structure(s)** (PDB): [2FIM](https://www.rcsb.org/structure/2FIM), [3C5N](https://www.rcsb.org/structure/3C5N).

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

*Describes the biological roles of TULP1 (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:** TULP1's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding. p.Val286fs falls in the disordered region.


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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, actin filament binding.

**Biological process:** retina homeostasis, positive regulation of phagocytosis, detection of light stimulus involved in visual perception.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-03-18.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-09-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-18 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, Leber congenital amaurosis, not provided, Leber's amaurosis, none provided.

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [TULP1 p.Val286Met](/variant/tulp1-p-val286met), [TULP1 c.1495+2dup](/variant/tulp1-c-1495-plus-2dup), [TULP1 p.Ile139fs](/variant/tulp1-p-ile139fs), [TULP1 p.Lys333fs](/variant/tulp1-p-lys333fs), [TULP1 c.1496-6C>A](/variant/tulp1-c-1496-minus-6c-a), [TULP1 p.Arg311Gln](/variant/tulp1-p-arg311gln), [TULP1 p.Arg311Trp](/variant/tulp1-p-arg311trp), [TULP1 p.Arg400Gln](/variant/tulp1-p-arg400gln).

### 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 505327). 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.*