PLEKHM2 p.Pro449=
c.1347G>A · rs1257493374 · VCV788228
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00222%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1 | GERP -3.6 |
| Overall | ||
| CADD | 4.423 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00222%
South Asian · 2/89,970 alleles
Filtering AF
0.000369%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000159%
Overall
0.00056%
9/1,605,730 alleles · very rare
exomes 9/1,453,506 · genomes 0/152,224 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00222% | 44,985 |
| European (non-Finnish) | 0.000595% | 168,120 |
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.Pro449=
- Coding
- c.1347G>A
- MANE Select
- NM_015164
- dbSNP
- rs1257493374
- Type
- single nucleotide variant
- Location
- chr1:15727419 (GRCh38)
- Gene constraint
- LOEUF 1.086 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 65.68 · 4 PDB
- Residue 449
- the 'disordered' region
Similar variants
- PLEKHM2 p.Pro449Leu 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
- PLEKHM2 p.Arg1012Gln 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-pro449 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown