Is PLCB1 p.Ser491Arg (c.1473T>A) pathogenic?

PLCB1 p.Ser491Arg (c.1473T>A) is classified Uncertain significance in PLCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-02). AlphaMissense: likely pathogenic (0.6602); Very rare (popmax 0.0011%, sas); Associated with developmental and epileptic encephalopathy, 12.

What condition is associated with PLCB1 p.Ser491Arg (c.1473T>A)?

PLCB1 p.Ser491Arg (c.1473T>A) is associated with developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Ser491Arg (c.1473T>A) in the general population?

PLCB1 p.Ser491Arg (c.1473T>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PLCB1 p.Ser491Arg (c.1473T>A)?

AlphaMissense predicts likely pathogenic (score 0.6602) — an in-silico prediction, not a clinical call.

PLCB1 p.Ser491Arg

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.1473T>A · rs2123468950 · VCV1484895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 12

Computational evidence

Protein change
AlphaMissense	0.6602	likely pathogenic
REVEL	0.265	benign-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -5
Regional constraint	o/e 0.84	unconstrained · MANE · 9,618 bp · p 0.07 · regional, not allelic
Overall
CADD	1.459	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 0.0011% South Asian · 1/91,018 alleles

Overall 6.2e-05% 1/1,613,742 alleles · very rare exomes 1/1,461,440 · genomes 0/152,302 · 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.Ser491Arg
Coding: c.1473T>A
MANE Select: NM_015192
dbSNP: rs2123468950
Type: single nucleotide variant
Location: chr20:8717808 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55
Residue 491: the 'disordered' region

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-ser491arg (accessed [today's date]).

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