Is ASL p.Arg456Gln (c.1367G>A) pathogenic?

ASL p.Arg456Gln (c.1367G>A) is classified Pathogenic/Likely pathogenic in ASL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.1005); Ultra-rare (popmax 0.015%, amr); Associated with argininosuccinic aciduria.

What condition is associated with ASL p.Arg456Gln (c.1367G>A)?

ASL p.Arg456Gln (c.1367G>A) is associated with argininosuccinic aciduria (ClinVar).

How common is ASL p.Arg456Gln (c.1367G>A) in the general population?

ASL p.Arg456Gln (c.1367G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is Argininosuccinic aciduria inherited?

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

What do computational predictors say about ASL p.Arg456Gln (c.1367G>A)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

ASL p.Arg456Gln

c.1367G>A · rs767271619 · VCV551210

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

argininosuccinic aciduria

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign ⚠ discordant with ClinVar
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.55	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.2	GERP 4.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	25.1	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 0.015% Admixed American · 9/59,982 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.0013% 21/1,610,384 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,665
African / African-American	0.00267%	37,468
European (non-Finnish)	0.000848%	117,990

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: ASL
Protein: p.Arg456Gln
Coding: c.1367G>A
MANE Select: NM_000048
dbSNP: rs767271619
Type: single nucleotide variant
Location: chr7:66092884 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB
Residue 456: an α-helix; a UniProt-annotated variant site (in arginsa); a UniProt-annotated variant site (in arginsa; reduction of argininosuccinate lyase activity; reduces protein expression)

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

Disease context

argininosuccinic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Argininosuccinic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ASL p.Arg456Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
ASL p.Arg456= Likely benign ★ same residue
ASL c.1062+5G>C Likely pathogenic ★★ same condition
ASL c.1143+1G>T Pathogenic/Likely pathogenic ★★ same condition
ASL c.13-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASL c.291+1G>T Likely pathogenic ★★ same condition
ASL c.348+1G>A Pathogenic/Likely pathogenic ★★ same condition
ASL c.349-1G>A 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/asl-p-arg456gln (accessed [today's date]).

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