Is TACSTD2 p.Leu186Pro (c.557T>C) pathogenic?

TACSTD2 p.Leu186Pro (c.557T>C) is classified Pathogenic in TACSTD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-01-01). AlphaMissense: likely pathogenic (0.9459); Very rare (popmax 8.48e-05%, nfe); Associated with gelatinous drop-like corneal dystrophy.

What condition is associated with TACSTD2 p.Leu186Pro (c.557T>C)?

TACSTD2 p.Leu186Pro (c.557T>C) is associated with gelatinous drop-like corneal dystrophy (ClinVar).

How common is TACSTD2 p.Leu186Pro (c.557T>C) in the general population?

TACSTD2 p.Leu186Pro (c.557T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Gelatinous drop-like corneal dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TACSTD2 p.Leu186Pro (c.557T>C)?

AlphaMissense predicts likely pathogenic (score 0.9459) — an in-silico prediction, not a clinical call.

TACSTD2 p.Leu186Pro

c.557T>C · rs80358228 · VCV16189

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gelatinous drop-like corneal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9459	likely pathogenic ✓ concordant with ClinVar · top 9% in TACSTD2
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -15.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 968 bp · p 0.067 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,522 alleles

Overall 6.2e-05% 1/1,612,346 alleles · very rare exomes 1/1,459,992 · genomes 0/152,354 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TACSTD2
Protein: p.Leu186Pro
Coding: c.557T>C
MANE Select: NM_002353
dbSNP: rs80358228
Type: single nucleotide variant
Location: chr1:58576600 (GRCh38)
Gene constraint: LOEUF 1.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 7 PDB

Full TACSTD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

gelatinous drop-like corneal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Gelatinous drop-like corneal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

TACSTD2 c.-56C>G Uncertain significance ★★ same condition
TACSTD2 p.Gly276Asp Uncertain significance ★★ ⚠ same condition
TACSTD2 p.Gly59Ser Uncertain significance ★★ ⚠ same condition
TACSTD2 c.-169G>A Benign ★★ same condition
TACSTD2 c.-54A>C Benign ★★ same condition
TACSTD2 c.*202A>G Benign ★★ same condition
TACSTD2 c.*280T>C Benign ★★ same condition
TACSTD2 c.*396T>C Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tacstd2-p-leu186pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown