Is PLEKHM2 p.Pro379= (c.1137G>A) pathogenic?

PLEKHM2 p.Pro379= (c.1137G>A) is classified Likely benign in PLEKHM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). Very rare (popmax 8.49e-05%, nfe).

How common is PLEKHM2 p.Pro379= (c.1137G>A) in the general population?

PLEKHM2 p.Pro379= (c.1137G>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

PLEKHM2 p.Pro379=

c.1137G>A · rs2148371752 · VCV1618350

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

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 -0.55	GERP -3.6
Overall
CADD	6.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,568 alleles

Overall 0.000124% 2/1,606,872 alleles · very rare exomes 2/1,454,718 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,204
European (non-Finnish)grpmax	8.49e-05%	1,177,568

Remaining individuals 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: PLEKHM2
Protein: p.Pro379=
Coding: c.1137G>A
MANE Select: NM_015164
dbSNP: rs2148371752
Type: single nucleotide variant
Location: chr1:15727209 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.68 · 4 PDB
Residue 379: the 'disordered' region

Full PLEKHM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLEKHM2 p.Pro379Leu 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-pro379 (accessed [today's date]).

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