Is ADSL p.Arg396Cys (c.1186C>T) pathogenic?

ADSL p.Arg396Cys (c.1186C>T) is classified Pathogenic/Likely pathogenic in ADSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.988); Very rare (popmax 0.0033%, sas); Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Arg396Cys (c.1186C>T)?

ADSL p.Arg396Cys (c.1186C>T) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Arg396Cys (c.1186C>T) in the general population?

ADSL p.Arg396Cys (c.1186C>T) is very rare (popmax 0.0033%, sas) (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.Arg396Cys (c.1186C>T)?

AlphaMissense predicts likely pathogenic (score 0.988) — an in-silico prediction, not a clinical call.

ADSL p.Arg396Cys

c.1186C>T · rs755492501 · VCV838200

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adenylosuccinate lyase deficiency

Computational evidence

Protein change
AlphaMissense	0.988	likely pathogenic ✓ concordant with ClinVar · top 10% in ADSL
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -16.73	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 4.9	GERP 1.4, 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 0.0033% South Asian · 3/90,970 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,588 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,323
European (non-Finnish)	0.00136%	73,743

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.Arg396Cys
Coding: c.1186C>T
MANE Select: NM_000026
dbSNP: rs755492501
Type: single nucleotide variant
Location: chr22:40364360 (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 396: a UniProt-annotated variant site (in adsld; severe; abolishes cooperativity and reduces enzyme activity); 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.Arg396His Pathogenic/Likely pathogenic ★★ same residue
ADSL p.Arg396fs 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.Arg141Trp Pathogenic/Likely pathogenic ★★ same condition
ADSL p.Arg149Ter 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-arg396cys (accessed [today's date]).

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