# NM_002353.3(TACSTD2):c.509C>A (p.Ser170Ter)

https://sugi.bio/variant/tacstd2-p-ser170ter

## Summary

**TACSTD2 p.Ser170Ter (c.509C>A)** is classified **Pathogenic** in TACSTD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 1999-04-01). No allele count reported in gnomAD v4.1 (AN 1,607,490); Associated with gelatinous drop-like corneal dystrophy.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs80358225 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,607,490)

## 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.Ser170Ter |
| Coding change (HGVS c.) | c.509C>A |
| MANE Select transcript | [NM_002353](https://www.ncbi.nlm.nih.gov/nuccore/NM_002353) |
| dbSNP | [rs80358225](https://www.ncbi.nlm.nih.gov/snp/rs80358225/) |
| Variant type | single nucleotide variant |
| Location | chr1:58576648-58576648 (GRCh38) |
| ClinVar | [VCV16184](https://www.ncbi.nlm.nih.gov/clinvar/variation/16184/) |

**All HGVS expressions:** `NC_000001.10:g.59042320G>T`, `NC_000001.11:g.58576648G>T`, `NG_016237.1:g.5847C>A`, `NM_002353.3:c.509C>A`

## 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 9.489, GERP 0.918, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 38.0**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,607,490)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **170** 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 1999-04-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1999-04-01 |

## 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 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), [TACSTD2 c.-54A>C](/variant/tacstd2-c-minus-54a-c), [TACSTD2 c.*202A>G](/variant/tacstd2-c-star-202a-g), [TACSTD2 c.*280T>C](/variant/tacstd2-c-star-280t-c), [TACSTD2 c.*396T>C](/variant/tacstd2-c-star-396t-c).

### 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 16184). 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.*