Is ASPH p.Trp594Ter (c.1782G>A) pathogenic?

ASPH p.Trp594Ter (c.1782G>A) is classified Pathogenic in ASPH (ClinVar, Single submitter, 1 submitter). Very rare (popmax 8.48e-05%, nfe); Associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome.

How common is ASPH p.Trp594Ter (c.1782G>A) in the general population?

ASPH p.Trp594Ter (c.1782G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ASPH p.Trp594Ter

Q: What condition is associated with ASPH p.Trp594Ter (c.1782G>A)?

ASPH p.Trp594Ter (c.1782G>A) is associated with facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (ClinVar).

c.1782G>A · rs749202132 · VCV1210220

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

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

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/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 25
Splicing
SpliceAI	Δ0.21	acceptor loss · deltas
Pangolin	Δ0.26	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	44.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,884 alleles

Overall 6.84e-05% 1/1,461,686 alleles · very rare

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.Trp594Ter
Coding: c.1782G>A
MANE Select: NM_004318
dbSNP: rs749202132
Type: single nucleotide variant
Location: chr8:61526095 (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 594: an α-helix

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.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
ASPH c.2127-6C>T 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-trp594ter (accessed [today's date]).

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