Is PLCB1 p.Pro875His (c.2624C>A) pathogenic?

PLCB1 p.Pro875His (c.2624C>A) is classified Uncertain significance in PLCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-17). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.00223%, eas); Associated with developmental and epileptic encephalopathy, 12.

What condition is associated with PLCB1 p.Pro875His (c.2624C>A)?

PLCB1 p.Pro875His (c.2624C>A) is associated with developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Pro875His (c.2624C>A) in the general population?

PLCB1 p.Pro875His (c.2624C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PLCB1 p.Pro875His (c.2624C>A)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

PLCB1 p.Pro875His

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.2624C>A · rs1386644525 · VCV1047578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 12

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.95	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 140 kb · p 0.025 · regional, not allelic
Overall
CADD	23.8	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 0.00223% East Asian · 1/44,860 alleles

Overall 6.85e-05% 1/1,460,650 alleles · very rare

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.Pro875His
Coding: c.2624C>A
MANE Select: NM_015192
dbSNP: rs1386644525
Type: single nucleotide variant
Location: chr20:8757146 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55
Residue 875: 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.Pro875Ser Uncertain significance ★★ ⚠ same residue
PLCB1 p.Pro875= Likely benign ★ 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

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-pro875his (accessed [today's date]).

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