# NM_003322.6(TULP1):c.1444C>T (p.Arg482Trp)

https://sugi.bio/variant/tulp1-p-arg482trp

## Summary

**TULP1 p.Arg482Trp (c.1444C>T)** is classified **Conflicting classifications of pathogenicity** in TULP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.9668); Very rare (popmax 0.004%, afr); Associated with TULP1-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs121909077 · 5 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the TULP1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to TULP1-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 | [TULP1](https://sugi.bio/atlas/gene/TULP1/) |
| Protein change (HGVS p.) | p.Arg482Trp |
| Coding change (HGVS c.) | c.1444C>T |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs121909077](https://www.ncbi.nlm.nih.gov/snp/rs121909077/) |
| Variant type | single nucleotide variant |
| Location | chr6:35500032-35500032 (GRCh38) |
| ClinVar | [VCV7363](https://www.ncbi.nlm.nih.gov/clinvar/variation/7363/) |

**All HGVS expressions:** `NC_000006.11:g.35467809G>A`, `NC_000006.12:g.35500032G>A`, `NG_009077.1:g.17839C>T`, `NM_001289395.2:c.1285C>T`, `NM_003322.6:c.1444C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9668)
- REVEL 0.966 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.982 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.158, GERP 2.08, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 1.02** across the covering region of the MANE Select transcript (35,498,330–35,506,278), spanning 7,948 bp. Chi-square p 0.64. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00111% · FAF99 0.0009% · 3/74,918 in the highest group · 32/1,614,048 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00937% | 10,670 |
| African / African-American (grpmax) | 0.004% | 24,973 |
| South Asian | 0.00329% | 30,360 |
| European (non-Finnish) | 0.00169% | 59,002 |

Finnish 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 **482** lies in a UniProt-annotated variant site (in rp14).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-31.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Uncertain significance).

**Submission history:** 5 submissions (2007–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2007-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-31 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-02 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-12 |

## Associated conditions {#conditions}

[TULP1-related disorder](https://sugi.bio/atlas/disease/tulp1-related-disorder/), [retinitis pigmentosa 14](https://sugi.bio/atlas/disease/retinitis-pigmentosa-14/), [Leber congenital amaurosis](https://sugi.bio/atlas/disease/leber-congenital-amaurosis/).

**Reported phenotype names (ClinVar):** TULP1-related disorder, Retinitis pigmentosa 14, not provided, Leber congenital amaurosis, TULP1-related disorders, TULP1-related condition, none provided, Leber's amaurosis, RETINITIS PIGMENTOSA, JUVENILE, TULP1-RELATED.

## Same-residue context {#hotspot}

Residue **482** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TULP1 p.Arg482Leu](/variant/tulp1-p-arg482leu), [TULP1 p.Arg482Gln](/variant/tulp1-p-arg482gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [TULP1 p.Arg482Gln](/variant/tulp1-p-arg482gln), [TULP1 p.Arg482Leu](/variant/tulp1-p-arg482leu), [TULP1 c.1112+1G>A](/variant/tulp1-c-1112-plus-1g-a), [TULP1 c.1495+1G>A](/variant/tulp1-c-1495-plus-1g-a), [TULP1 c.1496-6C>A](/variant/tulp1-c-1496-minus-6c-a), [TULP1 c.718+2T>C](/variant/tulp1-c-718-plus-2t-c), [TULP1 c.99+1G>A](/variant/tulp1-c-99-plus-1g-a), [TULP1 c.999+5G>C](/variant/tulp1-c-999-plus-5g-c).

### 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 7363). 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.*