Is ASS1 p.Ala10Pro (c.28G>C) pathogenic?

ASS1 p.Ala10Pro (c.28G>C) is classified Uncertain significance in ASS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.977); Very rare (popmax 0.00133%, afr); Associated with citrullinemia.

What condition is associated with ASS1 p.Ala10Pro (c.28G>C)?

ASS1 p.Ala10Pro (c.28G>C) is associated with citrullinemia (ClinVar).

How common is ASS1 p.Ala10Pro (c.28G>C) in the general population?

ASS1 p.Ala10Pro (c.28G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ASS1 p.Ala10Pro (c.28G>C)?

AlphaMissense predicts likely pathogenic (score 0.977) — an in-silico prediction, not a clinical call.

ASS1 p.Ala10Pro

c.28G>C · rs1845345016 · VCV842451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

citrullinemia

Computational evidence

Protein change
AlphaMissense	0.977	likely pathogenic
REVEL	0.989	strongly pathogenic-leaning
SaProt	LLR -14.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.38	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 49 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,052 alleles

Overall 6.84e-05% 1/1,461,882 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: ASS1
Protein: p.Ala10Pro
Coding: c.28G>C
MANE Select: NM_054012
dbSNP: rs1845345016
Type: single nucleotide variant
Location: chr9:130452256 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB
Residue 10: a binding site; a β-strand

Full ASS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

citrullinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASS1 c.1194-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.174+1G>A Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.174+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.175-1119G>A Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.364-2A>T Likely pathogenic ★★ same condition
ASS1 c.421-2A>G Pathogenic ★★ same condition
ASS1 c.496-2A>G Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.689-2A>C Pathogenic/Likely pathogenic ★★ 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/ass1-p-ala10pro (accessed [today's date]).

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