# NM_002353.3(TACSTD2):c.653del (p.Asp218fs)

https://sugi.bio/variant/tacstd2-p-asp218fs

## Summary

**TACSTD2 p.Asp218fs (c.653del)** is classified **Pathogenic** in TACSTD2 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00267%, afr); Associated with gelatinous drop-like corneal dystrophy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs780819073 · 1 submitter · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the TACSTD2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to gelatinous drop-like corneal dystrophy.

*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 recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Diagnostic panels | TACSTD2 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Gelatinous drop-like corneal dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Photophobia — Very frequent (99-80%)
- Blurred vision — Very frequent (99-80%)
- Blepharospasm — Frequent (79-30%)
- Reduced visual acuity — Frequent (79-30%)
- Subepithelial corneal opacities — Frequent (79-30%)
- Epiphora — Frequent (79-30%)
- Conjunctival amyloidosis — Frequent (79-30%)
- Corneal neovascularization — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009647/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TACSTD2](https://sugi.bio/atlas/gene/TACSTD2/) |
| Protein change (HGVS p.) | p.Asp218fs |
| Coding change (HGVS c.) | c.653del |
| MANE Select transcript | [NM_002353](https://www.ncbi.nlm.nih.gov/nuccore/NM_002353) |
| dbSNP | [rs780819073](https://www.ncbi.nlm.nih.gov/snp/rs780819073/) |
| Variant type | Deletion |
| Location | chr1:58576504-58576504 (GRCh38) |
| ClinVar | [VCV1699935](https://www.ncbi.nlm.nih.gov/clinvar/variation/1699935/) |

**All HGVS expressions:** `NC_000001.10:g.59042176del`, `NC_000001.11:g.58576504del`, `NG_016237.1:g.5991del`, `NM_002353.2:c.653del`, `NM_002353.3:c.653del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.31, GERP -4.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.868, pLI 3.6277e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.*
- 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000211% · 2/74,912 in the highest group · 10/1,613,078 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,456 |
| European (non-Finnish) | 0.000678% | 147,467 |

*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}

**TACSTD2** population constraint: LOEUF 1.868, pLI 3.6277e-06, missense-Z -1.56; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **218** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 83.11, 61% of residues very-high.

**7 experimental structure(s)** (PDB): [2MAE](https://www.rcsb.org/structure/2MAE), [2MVK](https://www.rcsb.org/structure/2MVK), [2MVL](https://www.rcsb.org/structure/2MVL), [7E5M](https://www.rcsb.org/structure/7E5M), [7E5N](https://www.rcsb.org/structure/7E5N), [7PEE](https://www.rcsb.org/structure/7PEE).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genomics, Lopukhin Federal Research and Clinical Center of Physical-chemical Medicine of the Federal Medical Biological Agency | Pathogenic | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

[gelatinous drop-like corneal dystrophy](https://sugi.bio/atlas/disease/gelatinous-drop-like-corneal-dystrophy/).

**Reported phenotype names (ClinVar):** Gelatinous droplike corneal dystrophy, AMYLOID CORNEAL DYSTROPHY, JAPANESE TYPE.

## Similar variants {#similar}

Related TACSTD2 variant pages (same residue, condition, or type): [TACSTD2 p.Asp218Gly](/variant/tacstd2-p-asp218gly), [TACSTD2 p.Asp218His](/variant/tacstd2-p-asp218his), [TACSTD2 p.Asp47_Pro49del](/variant/tacstd2-p-asp47-pro49del), [TACSTD2 p.Gln211fs](/variant/tacstd2-p-gln211fs), [TACSTD2 c.-56C>G](/variant/tacstd2-c-minus-56c-g), [TACSTD2 p.Gly276Asp](/variant/tacstd2-p-gly276asp), [TACSTD2 p.Gly59Ser](/variant/tacstd2-p-gly59ser), [TACSTD2 c.-169G>A](/variant/tacstd2-c-minus-169g-a).

### 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 1699935). 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.*