Is PLCE1 p.Ser47Arg (c.139A>C) pathogenic?

PLCE1 p.Ser47Arg (c.139A>C) is classified Uncertain significance in PLCE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.1179); Ultra-rare (popmax 0.0507%, afr); Associated with nephrotic syndrome, type 3.

What condition is associated with PLCE1 p.Ser47Arg (c.139A>C)?

PLCE1 p.Ser47Arg (c.139A>C) is associated with nephrotic syndrome, type 3 (ClinVar).

How common is PLCE1 p.Ser47Arg (c.139A>C) in the general population?

PLCE1 p.Ser47Arg (c.139A>C) is ultra-rare (popmax 0.0507%, afr) (gnomAD).

What do computational predictors say about PLCE1 p.Ser47Arg (c.139A>C)?

AlphaMissense predicts likely benign (score 0.1179) — an in-silico prediction, not a clinical call.

PLCE1 p.Ser47Arg

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.139A>C · rs752895021 · VCV2168985

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1179 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0507%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 3

Computational evidence

Protein change
AlphaMissense	0.1179	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.92	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 1.6	GERP -1.1, phastCons 0.43
Regional constraint	o/e 1.04	unconstrained · MANE · 975 bp · p 0.46 · regional, not allelic
Overall
CADD	11.06	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 0.0507% African / African-American · 38/74,896 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00273% 44/1,613,754 alleles · ultra-rare exomes 20/1,461,590 · genomes 24/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0507%	1,971
Admixed American	0.005%	19,986
Remaining individualsnot grpmax-eligible	0.0032%	31,235
European (non-Finnish)	8.48e-05%	1,179,874

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.Ser47Arg
Coding: c.139A>C
MANE Select: NM_016341
dbSNP: rs752895021
Type: single nucleotide variant
Location: chr10:94031185 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB

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-ser47arg (accessed [today's date]).

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