Is PLCE1 p.Pro728= (c.2184G>A) pathogenic?

PLCE1 p.Pro728= (c.2184G>A) is classified Conflicting classifications of pathogenicity in PLCE1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-12). Very rare (popmax 0.00941%, nfe); Associated with nephrotic syndrome, type 3.

What condition is associated with PLCE1 p.Pro728= (c.2184G>A)?

PLCE1 p.Pro728= (c.2184G>A) is associated with nephrotic syndrome, type 3 (ClinVar).

How common is PLCE1 p.Pro728= (c.2184G>A) in the general population?

PLCE1 p.Pro728= (c.2184G>A) is very rare (popmax 0.00941%, nfe) (gnomAD).

PLCE1 p.Pro728=

Q: How is Hereditary steroid-resistant nephrotic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2184G>A · rs760049549 · VCV880505

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00941%, nfe)

Conditions

nephrotic syndrome, type 3

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 -3.7	GERP -4.3
Overall
CADD	0.284	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00941% European (non-Finnish) · 111/1,180,002 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00756% 122/1,613,970 alleles · very rare exomes 116/1,461,796 · genomes 6/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00941%	10,631
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0064%	15,618
African / African-American	0.00267%	37,461
South Asian	0.0011%	91,076

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: PLCE1
Protein: p.Pro728=
Coding: c.2184G>A
MANE Select: NM_016341
dbSNP: rs760049549
Type: single nucleotide variant
Location: chr10:94234282 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB
Residue 728: the ras-gef domain

Full PLCE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome, type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary steroid-resistant nephrotic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

PLCE1 p.Pro728Leu Uncertain significance ★ ⚠ same residue
PLCE1 c.4506+1G>A Likely pathogenic ★★ same condition
PLCE1 c.6132+1G>A Likely pathogenic ★★ same condition
PLCE1 p.Arg1246Ter Pathogenic ★★ same condition
PLCE1 p.Arg1434Gln Likely pathogenic ★★ same condition
PLCE1 p.Arg1495Ter Pathogenic/Likely pathogenic ★★ same condition
PLCE1 p.Arg321Ter Pathogenic ★★ same condition
PLCE1 p.Arg493Ter 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/plce1-p-pro728 (accessed [today's date]).

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