Is ASPH p.Trp728Ter (c.2181_2183dup) pathogenic?

ASPH p.Trp728Ter (c.21812183dup) is classified Pathogenic/Likely pathogenic in ASPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-21). Ultra-rare (popmax 0.0385%, sas); Associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome.

How common is ASPH p.Trp728Ter (c.2181_2183dup) in the general population?

ASPH p.Trp728Ter (c.2181_2183dup) is ultra-rare (popmax 0.0385%, sas) (gnomAD).

ASPH p.Trp728Ter

Q: What condition is associated with ASPH p.Trp728Ter (c.2181_2183dup)?

ASPH p.Trp728Ter (c.2181_2183dup) is associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (ClinVar).

c.2181_2183dup · rs765610535 · VCV1184947

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, sas)

Conditions

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (25 of 25) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% South Asian · 35/90,854 alleles

Filtering AF 0.0284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0026% 38/1,460,722 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0385%	2,596
Middle Eastern	0.0168%	5,968
European (non-Finnish)	0.00017%	589,797

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: ASPH
Protein: p.Trp728Ter
Coding: c.2181_2183dup
MANE Select: NM_004318
dbSNP: rs765610535
Type: Duplication
Location: chr8:61503452 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 43 PDB
Residue 728: a β-strand

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

Disease context

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPH p.Thr577fs Likely pathogenic ★ same condition
ASPH p.Arg735Trp Likely pathogenic ★★ same condition
ASPH p.Tyr565Ter Pathogenic/Likely pathogenic ★★ same condition
ASPH c.1150-57G>A Benign ★★ same condition
ASPH c.1301-79C>G Benign ★★ same condition
ASPH c.1437+27G>A Benign ★★ same condition
ASPH c.1626+10A>G Benign ★★ same condition
ASPH c.1900+6T>C 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/asph-p-trp728ter (accessed [today's date]).

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