Is ADSL p.Pro16Leu (c.47C>T) pathogenic?

ADSL p.Pro16Leu (c.47C>T) is classified Uncertain significance in ADSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.8068); Very rare (popmax 0.00168%, amr); Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Pro16Leu (c.47C>T)?

ADSL p.Pro16Leu (c.47C>T) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Pro16Leu (c.47C>T) in the general population?

ADSL p.Pro16Leu (c.47C>T) is very rare (popmax 0.00168%, amr) (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.Pro16Leu (c.47C>T)?

AlphaMissense predicts likely pathogenic (score 0.8068) — an in-silico prediction, not a clinical call.

ADSL p.Pro16Leu

c.47C>T · rs541051390 · VCV1018226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adenylosuccinate lyase deficiency

Computational evidence

Protein change
AlphaMissense	0.8068	likely pathogenic
REVEL	0.689	pathogenic-leaning
SaProt	LLR -10.95	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 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.74	unconstrained · MANE · 72 bp · p 1.5e-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 0.00168% Admixed American · 1/59,366 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00106% 17/1,608,832 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,366
European (non-Finnish)	0.00136%	73,627

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.Pro16Leu
Coding: c.47C>T
MANE Select: NM_000026
dbSNP: rs541051390
Type: single nucleotide variant
Location: chr22:40346605 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 4 PDB

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.Pro16Ser Uncertain significance ★ ⚠ 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.Arg141Trp Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg149Ter Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg190Gln 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/adsl-p-pro16leu (accessed [today's date]).

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