# NM_003322.6(TULP1):c.524dup (p.Pro176fs)

https://sugi.bio/variant/tulp1-p-pro176fs

## Summary

**TULP1 p.Pro176fs (c.524dup)** is classified **Pathogenic** in TULP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-02). Very rare (popmax 0.0011%, sas); Associated with Leber congenital amaurosis 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1327062642 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the TULP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Leber congenital amaurosis 1.

*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) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TULP1 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/0000635/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.Pro176fs |
| Coding change (HGVS c.) | c.524dup |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs1327062642](https://www.ncbi.nlm.nih.gov/snp/rs1327062642/) |
| Variant type | Duplication |
| Location | chr6:35509903-35509904 (GRCh38) |
| ClinVar | [VCV547179](https://www.ncbi.nlm.nih.gov/clinvar/variation/547179/) |

**All HGVS expressions:** `NC_000006.11:g.35477686dup`, `NC_000006.12:g.35509909dup`, `NG_009077.1:g.7967dup`, `NM_001289395.2:c.365dup`, `NM_003322.6:c.524dup`

## 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 -0.389, GERP -3.12 — 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 6 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 **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/91,058 in the highest group · 6/1,613,670 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,492 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,816 |
| South Asian (grpmax) | 0.0011% | 91,058 |
| European (non-Finnish) | 0.000254% | 393,314 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **176** 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.Pro176fs 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-11-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Australian Inherited Retinal Disease Registry & DNA Bank, Sir Charles Gairdner Hospital | Pathogenic | criteria provided, single submitter | research | 2017-11-02 |

## Associated conditions {#conditions}

[Leber congenital amaurosis 1](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-1/).

**Reported phenotype names (ClinVar):** Leber congenital amaurosis 1, Congenital absence of the rods and cones, Leber's congenital tapetoretinal degeneration, Leber's congenital tapetoretinal dysplasia, RETINAL BLINDNESS, CONGENITAL, AMAUROSIS CONGENITA OF LEBER I.

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [TULP1 p.Pro176=](/variant/tulp1-p-pro176), [TULP1 p.Pro176Ser](/variant/tulp1-p-pro176ser), [TULP1 p.Arg311Trp](/variant/tulp1-p-arg311trp), [TULP1 p.Ile259Thr](/variant/tulp1-p-ile259thr), [TULP1 p.Arg361Gln](/variant/tulp1-p-arg361gln), [TULP1 p.Gln301fs](/variant/tulp1-p-gln301fs), [TULP1 p.Thr55fs](/variant/tulp1-p-thr55fs), [TULP1 p.Val286fs](/variant/tulp1-p-val286fs).

### 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 547179). 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.*