Is ADSL p.Arg141Trp (c.421C>T) pathogenic?

ADSL p.Arg141Trp (c.421C>T) is classified Pathogenic/Likely pathogenic in ADSL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.5831); Ultra-rare (popmax 0.0109%, nfe); Associated with ADSL-related disorder.

What condition is associated with ADSL p.Arg141Trp (c.421C>T)?

ADSL p.Arg141Trp (c.421C>T) is associated with ADSL-related disorder, adenylosuccinate lyase deficiency (ClinVar).

How common is ADSL p.Arg141Trp (c.421C>T) in the general population?

ADSL p.Arg141Trp (c.421C>T) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about ADSL p.Arg141Trp (c.421C>T)?

AlphaMissense predicts likely pathogenic (score 0.5831) — an in-silico prediction, not a clinical call.

ADSL p.Arg141Trp

c.421C>T · rs756210458 · VCV204815

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ADSL-related disorder

Computational evidence

Protein change
AlphaMissense	0.5831	likely pathogenic ✓ concordant with ClinVar
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP 0.55, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 20 kb · p 5.6e-07 · regional, not allelic
Overall
CADD	28.5	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 0.0109% European (non-Finnish) · 129/1,180,008 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0088%

Overall 0.00805% 130/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,147
Admixed American	0.00167%	59,998

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.Arg141Trp
Coding: c.421C>T
MANE Select: NM_000026
dbSNP: rs756210458
Type: single nucleotide variant
Location: chr22:40354266 (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

ADSL-related disorder

Also linked: adenylosuccinate lyase deficiency

Similar variants

ADSL p.Arg141Pro Conflicting classifications of pathogenicity ★ 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-arg141trp (accessed [today's date]).

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