# NM_003322.6(TULP1):c.725_728del (p.Pro242fs)

https://sugi.bio/variant/tulp1-p-pro242fs

## Summary

**TULP1 p.Pro242fs (c.725_728del)** is classified **Pathogenic** in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-31). Very rare (popmax 0.000508%, nfe).

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs771723580 · 2 submitters · very rare (popmax 0.000508%, nfe)

## For patients & families {#patients}

This is a change in the TULP1 gene that is considered disease-causing, 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.Pro242fs |
| Coding change (HGVS c.) | c.725_728del |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs771723580](https://www.ncbi.nlm.nih.gov/snp/rs771723580/) |
| Variant type | Deletion |
| Location | chr6:35509303-35509306 (GRCh38) |
| ClinVar | [VCV198784](https://www.ncbi.nlm.nih.gov/clinvar/variation/198784/) |

**All HGVS expressions:** `NC_000006.11:g.35477080_35477083del`, `NC_000006.12:g.35509303_35509306del`, `NG_009077.1:g.8565_8568del`, `NM_001289395.2:c.566_569del`, `NM_003322.6:c.725_728del`

## 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 1.676, GERP -0.233, phastCons 1 — weakly conserved position
- 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 8 of 15**, so the transcript is predicted to undergo NMD.
- 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.*
- 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 **0.000508%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,958 in the highest group · 6/1,613,882 alleles overall — very rare (popmax 0.000508%, nfe).

*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 **242** 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.Pro242fs 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-31.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2015–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2015-04-03 |

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

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [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.Pro282fs](/variant/tulp1-p-pro282fs), [TULP1 p.Ser210fs](/variant/tulp1-p-ser210fs), [TULP1 p.Phe528fs](/variant/tulp1-p-phe528fs), [TULP1 c.1323+20_1323+34del](/variant/tulp1-c-1323-plus-20-1323-plus-34del).

### 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 2026-10-14); 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 198784). 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.*