Is ASL p.Arg94His (c.281G>A) pathogenic?

ASL p.Arg94His (c.281G>A) is classified Likely pathogenic in ASL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-14). AlphaMissense: ambiguous (0.3833); Very rare (popmax 0.00223%, eas); Associated with argininosuccinic aciduria.

What condition is associated with ASL p.Arg94His (c.281G>A)?

ASL p.Arg94His (c.281G>A) is associated with argininosuccinic aciduria (ClinVar).

How common is ASL p.Arg94His (c.281G>A) in the general population?

ASL p.Arg94His (c.281G>A) is very rare (popmax 0.00223%, eas) (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.Arg94His (c.281G>A)?

AlphaMissense predicts ambiguous (score 0.3833) — an in-silico prediction, not a clinical call.

ASL p.Arg94His

c.281G>A · rs777437569 · VCV550701

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

argininosuccinic aciduria

Computational evidence

Protein change
AlphaMissense	0.3833	ambiguous
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -11.57	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	29.0	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 0.00223% East Asian · 1/44,760 alleles

Overall 0.000248% 4/1,609,724 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,760
Remaining individualsnot grpmax-eligible	0.00161%	62,270
African / African-American	0.00134%	74,864
European (non-Finnish)	8.48e-05%	1,179,144

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.Arg94His
Coding: c.281G>A
MANE Select: NM_000048
dbSNP: rs777437569
Type: single nucleotide variant
Location: chr7:66082441 (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 94: a UniProt-annotated variant site (in arginsa; severe); a UniProt-annotated variant site (in arginsa); an α-helix

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.Arg94Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ASL p.Arg94Ser Likely pathogenic ★ same residue
ASL p.Arg94= Likely benign ★ same residue
ASL p.Arg94fs Pathogenic ★ 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

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-arg94his (accessed [today's date]).

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