Is ASL p.Arg151His (c.452G>A) pathogenic?

ASL p.Arg151His (c.452G>A) is classified Uncertain significance in ASL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-13). AlphaMissense: likely benign (0.0956); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with ASL p.Arg151His (c.452G>A)?

ASL p.Arg151His (c.452G>A) is associated with Inborn genetic diseases, argininosuccinic aciduria (ClinVar).

How common is ASL p.Arg151His (c.452G>A) in the general population?

ASL p.Arg151His (c.452G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about ASL p.Arg151His (c.452G>A)?

AlphaMissense predicts likely benign (score 0.0956) — an in-silico prediction, not a clinical call.

ASL p.Arg151His

c.452G>A · rs758359291 · VCV2139158

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0956	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP 1.7
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,064 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00384% 62/1,613,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Finnishnot grpmax-eligible	0.0409%	2,447
African / African-American	0.0254%	3,944
Remaining individualsnot grpmax-eligible	0.0064%	15,620
South Asian	0.00329%	30,361
East Asian	0.00223%	44,872
Admixed American	0.00167%	59,994
European (non-Finnish)	0.000424%	236,005

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.Arg151His
Coding: c.452G>A
MANE Select: NM_000048
dbSNP: rs758359291
Type: single nucleotide variant
Location: chr7:66086590 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: argininosuccinic aciduria

Similar variants

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
ASL c.446+1G>A Pathogenic ★★ same condition
ASL c.446+2T>C 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-arg151his (accessed [today's date]).

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