Is ASL p.Ala2Asp (c.5C>A) pathogenic?

ASL p.Ala2Asp (c.5C>A) is classified Uncertain significance in ASL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.1543); Very rare (popmax 0.00536%, afr); Associated with Inborn genetic diseases.

What condition is associated with ASL p.Ala2Asp (c.5C>A)?

ASL p.Ala2Asp (c.5C>A) is associated with Inborn genetic diseases, argininosuccinic aciduria (ClinVar).

How common is ASL p.Ala2Asp (c.5C>A) in the general population?

ASL p.Ala2Asp (c.5C>A) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about ASL p.Ala2Asp (c.5C>A)?

AlphaMissense predicts likely benign (score 0.1543) — an in-silico prediction, not a clinical call.

ASL p.Ala2Asp

c.5C>A · rs149918397 · VCV2189609

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1543	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	26.3	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 0.00536% African / African-American · 4/74,648 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000625% 10/1,599,634 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,662
Admixed American	0.00343%	29,153
Remaining individualsnot grpmax-eligible	0.00323%	30,953
European (non-Finnish)	0.00017%	586,930

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.Ala2Asp
Coding: c.5C>A
MANE Select: NM_000048
dbSNP: rs149918397
Type: single nucleotide variant
Location: chr7:66076086 (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 2: a modified residue (n-acetylalanine)

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-ala2asp (accessed [today's date]).

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