Is ADSL p.Arg141Pro (c.422G>C) pathogenic?

ADSL p.Arg141Pro (c.422G>C) is classified Conflicting classifications of pathogenicity in ADSL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.9713); Very rare (popmax 0.00223%, eas); Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Arg141Pro (c.422G>C)?

ADSL p.Arg141Pro (c.422G>C) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Arg141Pro (c.422G>C) in the general population?

ADSL p.Arg141Pro (c.422G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Adenylosuccinate lyase deficiency inherited?

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

What do computational predictors say about ADSL p.Arg141Pro (c.422G>C)?

AlphaMissense predicts likely pathogenic (score 0.9713) — an in-silico prediction, not a clinical call.

ADSL p.Arg141Pro

c.422G>C · rs563054392 · VCV1003470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adenylosuccinate lyase deficiency

Computational evidence

Protein change
AlphaMissense	0.9713	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 20 kb · p 5.6e-07 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,878 alleles

Overall 0.000274% 4/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,253
East Asiangrpmax	0.00223%	44,878
African / African-American	0.00133%	74,990

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: ADSL
Protein: p.Arg141Pro
Coding: c.422G>C
MANE Select: NM_000026
dbSNP: rs563054392
Type: single nucleotide variant
Location: chr22:40354267 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 4 PDB
Residue 141: a UniProt-annotated variant site (in adsld; severe); an α-helix

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

Disease context

adenylosuccinate lyase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Adenylosuccinate lyase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ADSL p.Arg141Trp Pathogenic/Likely pathogenic ★★ same residue
ADSL c.1191+5G>C Pathogenic/Likely pathogenic ★★ same condition
ADSL c.402+1G>T Likely pathogenic ★★ same condition
ADSL c.482+1G>C Likely pathogenic ★★ same condition
ADSL c.-49T>C Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg149Ter Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg190Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADSL p.Arg190Ter 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/adsl-p-arg141pro (accessed [today's date]).

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