Is ASPG p.Ala53Pro (c.157G>C) pathogenic?

ASPG p.Ala53Pro (c.157G>C) is classified Uncertain significance in ASPG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.2056); Ultra-rare (popmax 0.0357%, sas).

How common is ASPG p.Ala53Pro (c.157G>C) in the general population?

ASPG p.Ala53Pro (c.157G>C) is ultra-rare (popmax 0.0357%, sas) (gnomAD).

What do computational predictors say about ASPG p.Ala53Pro (c.157G>C)?

AlphaMissense predicts likely benign (score 0.2056) — an in-silico prediction, not a clinical call.

ASPG p.Ala53Pro

c.157G>C · VCV4643519

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2056 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2056	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -10.99	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.27, phastCons 0.43
Regional constraint	o/e 0.93	unconstrained · MANE · 27 kb · p 0.058 · regional, not allelic
Overall
CADD	14.72	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 0.0357% South Asian · 30/84,016 alleles

Filtering AF 0.0257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00202% 31/1,537,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0357%	2,801
Remaining individualsnot grpmax-eligible	0.00167%	59,942

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: ASPG
Protein: p.Ala53Pro
Coding: c.157G>C
MANE Select: NM_001080464
Type: single nucleotide variant
Location: chr14:104092707 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 2 PDB
Residue 53: the asparaginase/glutaminase domain; the 'asparaginase' region

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

Similar variants

ASPG p.Asp223= Benign ★★ same type
ASPG c.1620+1G>A Uncertain significance ★ same type
ASPG p.Ala315Gly Uncertain significance ★ ⚠ same type
ASPG p.Ala315Val Uncertain significance ★ ⚠ same type
ASPG p.Ala332Val Uncertain significance ★ ⚠ same type
ASPG p.Ala442Thr Uncertain significance ★ ⚠ same type
ASPG p.Ala4Thr Uncertain significance ★ ⚠ same type
ASPG p.Ala537Ser Uncertain significance ★ ⚠ 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/aspg-p-ala53pro (accessed [today's date]).

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