Is ASS1 p.Pro172Leu (c.515C>T) pathogenic?

ASS1 p.Pro172Leu (c.515C>T) is classified Uncertain significance in ASS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-30). AlphaMissense: likely benign (0.3095); Very rare (popmax 0.00439%, sas); Associated with citrullinemia type I.

What condition is associated with ASS1 p.Pro172Leu (c.515C>T)?

ASS1 p.Pro172Leu (c.515C>T) is associated with citrullinemia type I (ClinVar).

How common is ASS1 p.Pro172Leu (c.515C>T) in the general population?

ASS1 p.Pro172Leu (c.515C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

How is Citrullinemia type I inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ASS1 p.Pro172Leu (c.515C>T)?

AlphaMissense predicts likely benign (score 0.3095) — an in-silico prediction, not a clinical call.

ASS1 p.Pro172Leu

c.515C>T · rs372078387 · VCV365256

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

citrullinemia type I

Computational evidence

Protein change
AlphaMissense	0.3095	likely benign
REVEL	0.688	pathogenic-leaning
SaProt	LLR -11.13	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 49 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	23.8	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 0.00439% South Asian · 4/91,090 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00366% 59/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
South Asiangrpmax	0.00439%	22,773
European (non-Finnish)	0.00407%	24,584
African / African-American	0.004%	24,971
Admixed American	0.00333%	30,004

Amish 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: ASS1
Protein: p.Pro172Leu
Coding: c.515C>T
MANE Select: NM_054012
dbSNP: rs372078387
Type: single nucleotide variant
Location: chr9:130470853 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.64 · 1 PDB
Residue 172: a UniProt-annotated variant site (in ctln1)

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

Disease context

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

For Citrullinemia type I (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ASS1 p.Pro172Arg Uncertain significance ★★ ⚠ same residue
ASS1 p.Pro172= 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-pro172leu (accessed [today's date]).

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