# NM_003322.6(TULP1):c.192T>C (p.Ala64=)

https://sugi.bio/variant/tulp1-p-ala64

## Summary

**TULP1 p.Ala64= (c.192T>C)** is classified **Uncertain significance** in TULP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.000611%, nfe); Associated with retinitis pigmentosa.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs886061337 · 1 submitter · 2 linked conditions · very rare (popmax 0.000611%, nfe)

## 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 1 submitter, 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.Ala64= |
| Coding change (HGVS c.) | c.192T>C |
| MANE Select transcript | [NM_003322](https://www.ncbi.nlm.nih.gov/nuccore/NM_003322) |
| dbSNP | [rs886061337](https://www.ncbi.nlm.nih.gov/snp/rs886061337/) |
| Variant type | single nucleotide variant |
| Location | chr6:35511805-35511805 (GRCh38) |
| ClinVar | [VCV356475](https://www.ncbi.nlm.nih.gov/clinvar/variation/356475/) |

**All HGVS expressions:** `NC_000006.11:g.35479582A>G`, `NC_000006.12:g.35511805A>G`, `NG_009077.1:g.6066T>C`, `NM_001289395.2:c.190+375T>C`, `NM_003322.6:c.192T>C`

## 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 -6.064, GERP -2.06 — fast-evolving / accelerated position
- CADD: **PHRED 0.368**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.94 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000611%** (nfe) · FAF95 0.000254% · FAF99 0.000163% · 7/1,146,070 in the highest group · 7/1,548,008 alleles overall — very rare (popmax 0.000611%, 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 **64** 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.Ala64= 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

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

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [Leber congenital amaurosis 15](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-15/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, Leber congenital amaurosis 15.

## Similar variants {#similar}

Related TULP1 variant pages (same residue, condition, or type): [TULP1 p.Ala64Val](/variant/tulp1-p-ala64val), [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.99+1G>A](/variant/tulp1-c-99-plus-1g-a), [TULP1 p.Arg311Gln](/variant/tulp1-p-arg311gln), [TULP1 p.Arg311Trp](/variant/tulp1-p-arg311trp), [TULP1 p.Arg342Ter](/variant/tulp1-p-arg342ter), [TULP1 p.Arg34Ter](/variant/tulp1-p-arg34ter).

### 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 356475). 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.*