Is ADSL p.Ala2Val (c.5C>T) pathogenic?

ADSL p.Ala2Val (c.5C>T) is classified Conflicting classifications of pathogenicity in ADSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.2992); Ultra-rare (popmax 0.0382%, eas); Associated with adenylosuccinate lyase deficiency.

What condition is associated with ADSL p.Ala2Val (c.5C>T)?

ADSL p.Ala2Val (c.5C>T) is associated with adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Ala2Val (c.5C>T) in the general population?

ADSL p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.0382%, 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.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2992) — an in-silico prediction, not a clinical call.

ADSL p.Ala2Val

c.5C>T · rs143083947 · VCV204808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2992 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0382%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adenylosuccinate lyase deficiency

Computational evidence

Protein change
AlphaMissense	0.2992	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.74	unconstrained · MANE · 72 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0382% East Asian · 17/44,528 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.00193% 31/1,603,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0382%	2,619
South Asian	0.00223%	44,757
Finnishnot grpmax-eligible	0.00166%	60,394
Remaining individualsnot grpmax-eligible	0.00161%	62,022
European (non-Finnish)	0.00085%	117,643

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_000026
dbSNP: rs143083947
Type: single nucleotide variant
Location: chr22:40346563 (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 2: a modified residue (n-acetylalanine); a UniProt-annotated variant site (in adsld; severe)

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 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
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-ala2val (accessed [today's date]).

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