Is PLCB1 p.Ala396= (c.1188G>A) pathogenic?

PLCB1 p.Ala396= (c.1188G>A) is classified Conflicting classifications of pathogenicity in PLCB1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-17). Very rare (popmax 0.00891%, nfe); Associated with developmental and epileptic encephalopathy, 12.

What condition is associated with PLCB1 p.Ala396= (c.1188G>A)?

PLCB1 p.Ala396= (c.1188G>A) is associated with developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Ala396= (c.1188G>A) in the general population?

PLCB1 p.Ala396= (c.1188G>A) is very rare (popmax 0.00891%, nfe) (gnomAD).

PLCB1 p.Ala396=

Q: How is Epilepsy of infancy with migrating focal seizures inherited?

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

c.1188G>A · rs202109404 · VCV288753

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, nfe)

Conditions

developmental and epileptic encephalopathy, 12

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 -1.2	GERP -5.3
Overall
CADD	9.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% European (non-Finnish) · 105/1,178,706 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00701%

Overall 0.00707% 114/1,612,276 alleles · very rare exomes 105/1,460,162 · genomes 9/152,114 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00891%	11,226
African / African-American	0.00535%	18,707
Admixed American	0.00334%	29,974
Remaining individualsnot grpmax-eligible	0.00321%	31,200
East Asian	0.00223%	44,846

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: PLCB1
Protein: p.Ala396=
Coding: c.1188G>A
MANE Select: NM_015192
dbSNP: rs202109404
Type: single nucleotide variant
Location: chr20:8708690 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55
Residue 396: the pi-plc x-box domain

Full PLCB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epilepsy of infancy with migrating focal seizures (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

PLCB1 p.Ala396Val Uncertain significance ★ ⚠ same residue
PLCB1 p.Arg222Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 p.Arg815Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 c.3336+3A>G Uncertain significance ★★ same condition
PLCB1 p.Ala1046Ser Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1046Thr Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1182Val Uncertain significance ★★ ⚠ 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/plcb1-p-ala396 (accessed [today's date]).

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