AGRN p.Pro1001Ala
c.3001C>G · rs752212460 · VCV2741490
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0329%, mid)
Conditions
1
congenital myasthenic syndrome 8
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.083 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.38 | GERP 0.37 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 8,500 bp · p 0.41 · regional, not allelic |
| Overall | ||
| CADD | 4.049 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0329%
Middle Eastern · 2/6,080 alleles
Filtering AF
0.0058%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00312%
Overall
0.00261%
42/1,610,654 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0329% | 3,040 |
| South Asian | 0.0088% | 11,368 |
| East Asian | 0.0067% | 14,935 |
| Admixed American | 0.00334% | 29,944 |
| Remaining individualsnot grpmax-eligible | 0.00321% | 31,172 |
| African / African-American | 0.00267% | 37,430 |
| European (non-Finnish) | 0.00195% | 51,249 |
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
- AGRN
- Protein
- p.Pro1001Ala
- Coding
- c.3001C>G
- MANE Select
- NM_198576
- dbSNP
- rs752212460
- Type
- single nucleotide variant
- Location
- chr1:1046486 (GRCh38)
- Gene constraint
- LOEUF 0.73 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 69.79 · 1 PDB
- Residue 1001
- the 'disordered' region
Similar variants
- AGRN p.Pro1001Ser Uncertain significance ★★ same residue
- AGRN p.Pro1001= Likely benign ★★ same residue
- AGRN p.Pro1001Thr Conflicting classifications of pathogenicity ★ same residue
- AGRN c.3632-1G>C Likely pathogenic ★★ same condition
- AGRN p.Arg1671Ter Pathogenic/Likely pathogenic ★★ same condition
- AGRN p.Arg834Ter Pathogenic/Likely pathogenic ★★ same condition
- AGRN p.Gly1582Arg Pathogenic ★★ same condition
- AGRN p.Gly1675Ser Pathogenic/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/agrn-p-pro1001ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown