Is PLCE1 p.Phe1353= (c.4059C>T) pathogenic?

PLCE1 p.Phe1353= (c.4059C>T) is classified Benign/Likely benign in PLCE1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-19). Low-frequency (popmax 3%, afr); Associated with nephrotic syndrome, type 3.

What condition is associated with PLCE1 p.Phe1353= (c.4059C>T)?

PLCE1 p.Phe1353= (c.4059C>T) is associated with nephrotic syndrome, type 3, focal segmental glomerulosclerosis (ClinVar).

How common is PLCE1 p.Phe1353= (c.4059C>T) in the general population?

PLCE1 p.Phe1353= (c.4059C>T) is low-frequency (popmax 3%, afr) (gnomAD).

PLCE1 p.Phe1353=

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.4059C>T · rs61751499 · VCV260718

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3%, afr)

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 -5.9	GERP -4.6
Overall
CADD	1.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3% African / African-American · 2,245/74,868 alleles

Filtering AF 2.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.85%

Overall 0.194% 3,137/1,613,156 alleles · low-frequency exomes 1,757/1,461,240 · genomes 1,380/151,916 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3%	33
Remaining individualsnot grpmax-eligible	0.312%	320
Admixed American	0.308%	324
Middle Eastern	0.297%	337
East Asian	0.136%	735
South Asian	0.0923%	1,084
European (non-Finnish)	0.0294%	3,399
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,796

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.Phe1353=
Coding: c.4059C>T
MANE Select: NM_016341
dbSNP: rs61751499
Type: single nucleotide variant
Location: chr10:94265652 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB
Residue 1353: a UniProt-annotated variant site (in nphs3)

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

Also linked: focal segmental glomerulosclerosis

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-phe1353 (accessed [today's date]).

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