PLEKHM2 p.Pro490=
c.1470G>A · rs371661618 · VCV1100644
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0176%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.8, phastCons 1 |
| Overall | ||
| CADD | 15.7 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0176%
African / African-American · 13/74,034 alleles
Filtering AF
0.0104%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00822%
Overall
0.00159%
25/1,576,888 alleles · ultra-rare
exomes 16/1,425,072 · genomes 9/151,816 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0176% | 5,695 |
| Admixed American | 0.00928% | 10,774 |
| Remaining individualsnot grpmax-eligible | 0.00163% | 61,212 |
| South Asian | 0.00116% | 86,530 |
| European (non-Finnish) | 0.00043% | 232,386 |
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
- PLEKHM2
- Protein
- p.Pro490=
- Coding
- c.1470G>A
- MANE Select
- NM_015164
- dbSNP
- rs371661618
- Type
- single nucleotide variant
- Location
- chr1:15727542 (GRCh38)
- Gene constraint
- LOEUF 1.086 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 65.68 · 4 PDB
- Residue 490
- the 'disordered' region
Similar variants
- PLEKHM2 p.Pro490Gln Uncertain significance ★ ⚠ same residue
- PLEKHM2 p.Pro490Leu Uncertain significance ★ ⚠ same residue
- PLEKHM2 p.Ala252Thr Uncertain significance ★★ ⚠ same type
- PLEKHM2 p.Ala277Glu Uncertain significance ★★ ⚠ same type
- PLEKHM2 p.Ala339Thr Uncertain significance ★★ ⚠ same type
- PLEKHM2 p.Ala499Ser Uncertain significance ★★ ⚠ same type
- PLEKHM2 p.Ala689Val Uncertain significance ★★ ⚠ same type
- PLEKHM2 p.Arg1010His Uncertain significance ★★ ⚠ 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/plekhm2-p-pro490 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown