Is ASPH p.Pro121= (c.363A>G) pathogenic?

ASPH p.Pro121= (c.363A>G) is classified Likely benign in ASPH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-16). Ultra-rare (popmax 0.0834%, mid); Associated with ASPH-related disorder.

What condition is associated with ASPH p.Pro121= (c.363A>G)?

ASPH p.Pro121= (c.363A>G) is associated with ASPH-related disorder (ClinVar).

How common is ASPH p.Pro121= (c.363A>G) in the general population?

ASPH p.Pro121= (c.363A>G) is ultra-rare (popmax 0.0834%, mid) (gnomAD).

ASPH p.Pro121=

c.363A>G · rs144325115 · VCV3050232

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, mid)

Conditions

ASPH-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -4.2
Overall
CADD	0.883	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0834% Middle Eastern · 5/5,998 alleles

Filtering AF 0.0328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.00793% 128/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0834%	1,200
Remaining individualsnot grpmax-eligible	0.0144%	6,944
European (non-Finnish)	0.00949%	10,536
Admixed American	0.00333%	30,002

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.Pro121=
Coding: c.363A>G
MANE Select: NM_004318
dbSNP: rs144325115
Type: single nucleotide variant
Location: chr8:61653620 (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 121: the 'disordered' region

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

Disease context

ASPH-related disorder

Similar variants

ASPH p.Pro121Arg Uncertain significance ★ ⚠ same residue
ASPH p.Pro121Leu Uncertain significance ★ ⚠ same residue
ASPH p.Arg735Trp Likely pathogenic ★★ same condition
ASPH p.Arg735Gln Likely pathogenic ★ same condition
ASPH c.977-8T>C Likely benign same condition
ASPH p.Asp194Asn Likely benign same condition
ASPH p.His160= Likely benign same condition
ASPH p.Leu421= 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/asph-p-pro121 (accessed [today's date]).

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