Is PLCE1 p.Ala643Ser (c.1927G>T) pathogenic?

PLCE1 p.Ala643Ser (c.1927G>T) is classified Conflicting classifications of pathogenicity in PLCE1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.142); Rare (popmax 0.185%, nfe); Associated with nephrotic syndrome, type 3.

What condition is associated with PLCE1 p.Ala643Ser (c.1927G>T)?

PLCE1 p.Ala643Ser (c.1927G>T) is associated with nephrotic syndrome, type 3 (ClinVar).

How common is PLCE1 p.Ala643Ser (c.1927G>T) in the general population?

PLCE1 p.Ala643Ser (c.1927G>T) is rare (popmax 0.185%, nfe) (gnomAD).

What do computational predictors say about PLCE1 p.Ala643Ser (c.1927G>T)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

PLCE1 p.Ala643Ser

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.1927G>T · rs61886330 · VCV448042

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 3

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -3.57	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 3	GERP -0.93, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 214 kb · p 0.44 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.185% European (non-Finnish) · 2,179/1,179,912 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.161% 2,591/1,614,056 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.281%	356
Remaining individualsnot grpmax-eligible	0.211%	474
European (non-Finnish)grpmax	0.185%	541
South Asian	0.0637%	1,570
Admixed American	0.0283%	3,531
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
African / African-American	0.0227%	4,415

Finnish 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: PLCE1
Protein: p.Ala643Ser
Coding: c.1927G>T
MANE Select: NM_016341
dbSNP: rs61886330
Type: single nucleotide variant
Location: chr10:94227423 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB
Residue 643: 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.Ala643Thr 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-ala643ser (accessed [today's date]).

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