Is PLCB1 p.Lys681Arg (c.2042A>G) pathogenic?

PLCB1 p.Lys681Arg (c.2042A>G) is classified Uncertain significance in PLCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00549%, sas); Associated with developmental and epileptic encephalopathy, 12.

What condition is associated with PLCB1 p.Lys681Arg (c.2042A>G)?

PLCB1 p.Lys681Arg (c.2042A>G) is associated with developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Lys681Arg (c.2042A>G) in the general population?

PLCB1 p.Lys681Arg (c.2042A>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about PLCB1 p.Lys681Arg (c.2042A>G)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

PLCB1 p.Lys681Arg

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.2042A>G · rs776660417 · VCV1519696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 12

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	donor loss · deltas
Constraint at this position
Conservation	phyloP 9.3	GERP 2.7, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 9,827 bp · p 3.7e-20 · regional, not allelic
Overall
CADD	24.5	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 0.00549% South Asian · 5/91,060 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00031% 5/1,613,544 alleles · very rare exomes 5/1,461,234 · genomes 0/152,310 · 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: PLCB1
Protein: p.Lys681Arg
Coding: c.2042A>G
MANE Select: NM_015192
dbSNP: rs776660417
Type: single nucleotide variant
Location: chr20:8733391 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55
Residue 681: the c2 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.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
PLCB1 p.Ala155Val 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-lys681arg (accessed [today's date]).

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