Is ASPA p.Asn121Asp (c.361A>G) pathogenic?

ASPA p.Asn121Asp (c.361A>G) is classified Likely pathogenic in ASPA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-01). AlphaMissense: likely benign (0.2528); Very rare (popmax 0.00161%, nfe).

How common is ASPA p.Asn121Asp (c.361A>G) in the general population?

ASPA p.Asn121Asp (c.361A>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about ASPA p.Asn121Asp (c.361A>G)?

AlphaMissense predicts likely benign (score 0.2528) — an in-silico prediction, not a clinical call.

ASPA p.Asn121Asp

c.361A>G · rs148451498 · VCV1176650

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2528	likely benign ⚠ discordant with ClinVar
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -9.90	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	26.8	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 0.00161% European (non-Finnish) · 19/1,179,824 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,613,682 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,234
European (non-Finnish)grpmax	0.00161%	62,096

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ASPA
Protein: p.Asn121Asp
Coding: c.361A>G
MANE Select: NM_000049
dbSNP: rs148451498
Type: single nucleotide variant
Location: chr17:3481727 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB
Residue 121: a β-strand

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

Similar variants

ASPA p.Asn121= Likely benign ★ same residue
ASPA p.Asn121fs Likely pathogenic ★ same residue
ASPA c.236+2T>C Likely pathogenic ★★ same type
ASPA c.237-1G>T Likely pathogenic ★★ same type
ASPA c.237-2A>T Pathogenic/Likely pathogenic ★★ same type
ASPA c.527-1G>A Likely pathogenic ★★ same type
ASPA c.527-2A>C Likely pathogenic ★★ same type
ASPA c.527-2A>G Likely pathogenic ★★ same type

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/aspa-p-asn121asp (accessed [today's date]).

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