Is ASS1 p.Ala216Asp (c.647C>A) pathogenic?

ASS1 p.Ala216Asp (c.647C>A) is classified Uncertain significance in ASS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-30). AlphaMissense: likely pathogenic (0.8556); Very rare (popmax 0.00133%, afr); Associated with citrullinemia.

What condition is associated with ASS1 p.Ala216Asp (c.647C>A)?

ASS1 p.Ala216Asp (c.647C>A) is associated with citrullinemia, citrullinemia type I (ClinVar).

How common is ASS1 p.Ala216Asp (c.647C>A) in the general population?

ASS1 p.Ala216Asp (c.647C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ASS1 p.Ala216Asp (c.647C>A)?

AlphaMissense predicts likely pathogenic (score 0.8556) — an in-silico prediction, not a clinical call.

ASS1 p.Ala216Asp

c.647C>A · rs1043964127 · VCV813410

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8556 · 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	0.8556	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -13.88	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 5.2	GERP 0.63, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 49 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	24.1	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 · 1/75,032 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000752% 11/1,461,844 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,032
European (non-Finnish)	0.000847%	118,002

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: ASS1
Protein: p.Ala216Asp
Coding: c.647C>A
MANE Select: NM_054012
dbSNP: rs1043964127
Type: single nucleotide variant
Location: chr9:130476920 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB
Residue 216: a UniProt-annotated variant site (in ctln1)

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

Also linked: citrullinemia type I

Similar variants

ASS1 p.Ala216Thr Uncertain significance ★ ⚠ same residue
ASS1 p.Ala216= Likely benign ★ same residue
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>C Pathogenic/Likely pathogenic ★★ same condition
ASS1 c.364-2A>G 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-ala216asp (accessed [today's date]).

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