Is ASPH p.Arg735Trp (c.2203C>T) pathogenic?

ASPH p.Arg735Trp (c.2203C>T) is classified Likely pathogenic in ASPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-19). AlphaMissense: likely pathogenic (0.9692); Very rare (popmax 0.00533%, afr); Associated with Thoracic aortic aneurysm or dissection.

What condition is associated with ASPH p.Arg735Trp (c.2203C>T)?

ASPH p.Arg735Trp (c.2203C>T) is associated with Thoracic aortic aneurysm or dissection, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (ClinVar).

How common is ASPH p.Arg735Trp (c.2203C>T) in the general population?

ASPH p.Arg735Trp (c.2203C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about ASPH p.Arg735Trp (c.2203C>T)?

AlphaMissense predicts likely pathogenic (score 0.9692) — an in-silico prediction, not a clinical call.

ASPH p.Arg735Trp

c.2203C>T · rs374385878 · VCV137615

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Thoracic aortic aneurysm or dissection

Computational evidence

Protein change
AlphaMissense	0.9692	likely pathogenic ✓ concordant with ClinVar
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -14.84	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	33.0	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 0.00533% African / African-American · 4/74,992 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.0026% 42/1,612,920 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,748
South Asian	0.0033%	30,286
European (non-Finnish)	0.0028%	35,745
East Asian	0.00223%	44,772
Remaining individualsnot grpmax-eligible	0.0016%	62,432

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.Arg735Trp
Coding: c.2203C>T
MANE Select: NM_004318
dbSNP: rs374385878
Type: single nucleotide variant
Location: chr8:61503433 (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 735: a binding site; a UniProt-annotated variant site (in fdlab); a β-strand

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

Disease context

Thoracic aortic aneurysm or dissection

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

Similar variants

ASPH p.Arg735Gln Likely pathogenic ★ same residue
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-arg735trp (accessed [today's date]).

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