# NM_003322.6(TULP1):c.1581del (p.Phe528fs)

https://sugi.bio/variant/tulp1-p-phe528fs

## Summary

**TULP1 p.Phe528fs (c.1581del)** is classified **Uncertain significance** in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-12). Very rare (popmax 0.00892%, eas).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1355066758 · 2 submitters · very rare (popmax 0.00892%, eas)

## For patients & families {#patients}

This is a change in the TULP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [TULP1](https://sugi.bio/atlas/gene/TULP1/) |
| Protein change (HGVS p.) | p.Phe528fs |
| Coding change (HGVS c.) | c.1581del |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs1355066758](https://www.ncbi.nlm.nih.gov/snp/rs1355066758/) |
| Variant type | Deletion |
| Location | chr6:35498375-35498375 (GRCh38) |
| ClinVar | [VCV865996](https://www.ncbi.nlm.nih.gov/clinvar/variation/865996/) |

**All HGVS expressions:** `NC_000006.11:g.35466153del`, `NC_000006.12:g.35498376del`, `NG_009077.1:g.19496del`, `NM_001289395.2:c.1422del`, `NM_003322.6:c.1581del`

## 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 11.176, GERP 2.08, phastCons 1 — highly conserved position (PP3-type support)
- 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 the last exon (15 of 15)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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 **0.00892%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,860 in the highest group · 4/1,613,534 alleles overall — very rare (popmax 0.00892%, eas).

*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 **528** lies in an α-helix.

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.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-12.

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

**Submission history:** 2 submissions (2019–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-12 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [TULP1 p.Phe528=](/variant/tulp1-p-phe528), [TULP1 p.Arg419fs](/variant/tulp1-p-arg419fs), [TULP1 p.Gln485fs](/variant/tulp1-p-gln485fs), [TULP1 p.Leu504fs](/variant/tulp1-p-leu504fs), [TULP1 p.Lys274fs](/variant/tulp1-p-lys274fs), [TULP1 p.Pro242fs](/variant/tulp1-p-pro242fs), [TULP1 p.Pro282fs](/variant/tulp1-p-pro282fs), [TULP1 p.Ser210fs](/variant/tulp1-p-ser210fs).

### 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 865996). 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.*