Is TACSTD2 p.Asp216Glu (c.648C>A) pathogenic?

TACSTD2 p.Asp216Glu (c.648C>A) is classified Benign in TACSTD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2384); Common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with gelatinous drop-like corneal dystrophy.

What condition is associated with TACSTD2 p.Asp216Glu (c.648C>A)?

TACSTD2 p.Asp216Glu (c.648C>A) is associated with gelatinous drop-like corneal dystrophy (ClinVar).

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.Asp216Glu (c.648C>A)?

AlphaMissense predicts likely benign (score 0.2384) — an in-silico prediction, not a clinical call.

TACSTD2 p.Asp216Glu

Q: How common is TACSTD2 p.Asp216Glu (c.648C>A) in the general population?

TACSTD2 p.Asp216Glu (c.648C>A) is common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.648C>A · rs14008 · VCV297768

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2384 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gelatinous drop-like corneal dystrophy

Computational evidence

Protein change
AlphaMissense	0.2384	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.014	GERP -4.5, phastCons 0.54
Regional constraint	o/e 1.08	unconstrained · MANE · 968 bp · p 0.067 · regional, not allelic
Overall
CADD	15.52	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 32.9% African / African-American · 24,669/74,974 alleles

Filtering AF 32.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.4%

Overall 8.36% 134,772/1,612,390 alleles · common exomes 113,446/1,460,112 · genomes 21,326/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	32.9%	3
East Asian	12.3%	8
South Asian	9.38%	11
Ashkenazi Jewishnot grpmax-eligible	8.93%	11
Remaining individualsnot grpmax-eligible	8.54%	12
European (non-Finnish)	6.92%	14
Middle Eastern	5.37%	19
Finnishnot grpmax-eligible	5.19%	19
Amishnot grpmax-eligible	4.82%	21
Admixed American	4.65%	21

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.Asp216Glu
Coding: c.648C>A
MANE Select: NM_002353
dbSNP: rs14008
Type: single nucleotide variant
Location: chr1:58576509 (GRCh38)
Gene constraint: LOEUF 1.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 7 PDB
Residue 216: a UniProt-annotated variant site (in); an α-helix

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-asp216glu (accessed [today's date]).

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