Is PLCE1 p.Asp596Glu (c.1788T>A) pathogenic?

PLCE1 p.Asp596Glu (c.1788T>A) is classified Uncertain significance in PLCE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.2021); Ultra-rare (popmax 0.0468%, eas); Associated with nephrotic syndrome, type 3.

What condition is associated with PLCE1 p.Asp596Glu (c.1788T>A)?

PLCE1 p.Asp596Glu (c.1788T>A) is associated with nephrotic syndrome, type 3 (ClinVar).

How common is PLCE1 p.Asp596Glu (c.1788T>A) in the general population?

PLCE1 p.Asp596Glu (c.1788T>A) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about PLCE1 p.Asp596Glu (c.1788T>A)?

AlphaMissense predicts likely benign (score 0.2021) — an in-silico prediction, not a clinical call.

PLCE1 p.Asp596Glu

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.1788T>A · VCV3420030

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 3

Computational evidence

Protein change
AlphaMissense	0.2021	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.65	GERP -1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 214 kb · p 0.44 · regional, not allelic
Overall
CADD	19.43	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,878 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.0013% 21/1,614,114 alleles · ultra-rare exomes 19/1,461,800 · genomes 2/152,314 · joint denominator

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.Asp596Glu
Coding: c.1788T>A
MANE Select: NM_016341
Type: single nucleotide variant
Location: chr10:94171475 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB
Residue 596: 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 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
PLCE1 p.Gln1020Ter 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-asp596glu (accessed [today's date]).

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