Is PLCB4 p.Pro192Arg (c.575C>G) pathogenic?

PLCB4 p.Pro192Arg (c.575C>G) is classified Uncertain significance in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: likely pathogenic (0.8874); Very rare (popmax 6.29e-05%); Associated with Inborn genetic diseases.

What condition is associated with PLCB4 p.Pro192Arg (c.575C>G)?

PLCB4 p.Pro192Arg (c.575C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLCB4 p.Pro192Arg (c.575C>G) in the general population?

PLCB4 p.Pro192Arg (c.575C>G) is very rare (popmax 6.29e-05%) (gnomAD).

What do computational predictors say about PLCB4 p.Pro192Arg (c.575C>G)?

AlphaMissense predicts likely pathogenic (score 0.8874) — an in-silico prediction, not a clinical call.

PLCB4 p.Pro192Arg

c.575C>G · rs1244478803 · VCV2540760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.29e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8874	likely pathogenic
REVEL	0.429	indeterminate
SaProt	LLR -15.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 72 kb · p 0.00011 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 6.29e-05%

Overall 6.29e-05% 1/1,589,642 alleles · very rare exomes 0/1,437,612 · genomes 1/152,030 · 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: PLCB4
Protein: p.Pro192Arg
Coding: c.575C>G
MANE Select: NM_001377142
dbSNP: rs1244478803
Type: single nucleotide variant
Location: chr20:9371285 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03

Full PLCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCB4 p.Pro192Ser Uncertain significance ★ ⚠ same residue
PLCB4 p.Arg633His Pathogenic ★★ same condition
PLCB4 p.Arg640Gln Uncertain significance ★★ ⚠ same condition
PLCB4 p.Glu1005Lys Uncertain significance ★★ ⚠ same condition
PLCB4 p.Thr1016Met Uncertain significance ★★ ⚠ same condition
PLCB4 p.Val763Ile Uncertain significance ★★ ⚠ same condition
PLCB4 p.Ala1102Thr Uncertain significance ★ ⚠ same condition
PLCB4 p.Ala1102Val 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/plcb4-p-pro192arg (accessed [today's date]).

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