PMPCA p.Arg522Trp
c.1564C>T · rs1024902017 · VCV2885341
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3715 | ambiguous |
|---|---|---|
| REVEL | 0.235 | benign-leaning |
| SaProt | LLR -6.06 | tolerated |
| ⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 3.3 | GERP 1.3, phastCons 1 |
| Regional constraint | o/e 1.03 | unconstrained · MANE · 13 kb · p 0.42 · regional, not allelic |
| Overall | ||
| CADD | 28.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Finnishnot grpmax-eligible | 0.00638% | 15,670 |
| African / African-Americangrpmax | 0.004% | 24,977 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,223 |
| East Asian | 0.00223% | 44,882 |
| European (non-Finnish) | 0.00195% | 51,284 |
| Admixed American | 0.00167% | 59,948 |
| South Asian | 0.0011% | 91,064 |
Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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
- PMPCA
- Protein
- p.Arg522Trp
- Coding
- c.1564C>T
- MANE Select
- NM_015160
- dbSNP
- rs1024902017
- Type
- single nucleotide variant
- Location
- chr9:136423250 (GRCh38)
- Gene constraint
- LOEUF 1.111 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 88.46
Similar variants
- INPP5E p.Gly522Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
- PMPCA p.Arg522Gln Uncertain significance ★★ ⚠ same residue
- INPP5E p.Gly522Arg Likely pathogenic ★ same residue
- INPP5E c.937-2A>G Pathogenic/Likely pathogenic ★★ same type
- INPP5E p.Arg378Cys Pathogenic/Likely pathogenic ★★ same type
- INPP5E p.Arg435Gln Pathogenic/Likely pathogenic ★★ same type
- INPP5E p.Arg435Trp Pathogenic/Likely pathogenic ★★ same type
- INPP5E p.Arg557His Pathogenic/Likely pathogenic ★★ same type
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/pmpca-p-arg522trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown