Is PLCB4 p.Pro14Ala (c.40C>G) pathogenic?

PLCB4 p.Pro14Ala (c.40C>G) is classified Uncertain significance in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1433); Very rare (popmax 0.00077%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLCB4 p.Pro14Ala (c.40C>G)?

PLCB4 p.Pro14Ala (c.40C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLCB4 p.Pro14Ala (c.40C>G) in the general population?

PLCB4 p.Pro14Ala (c.40C>G) is very rare (popmax 0.00077%, nfe) (gnomAD).

What do computational predictors say about PLCB4 p.Pro14Ala (c.40C>G)?

AlphaMissense predicts likely benign (score 0.1433) — an in-silico prediction, not a clinical call.

PLCB4 p.Pro14Ala

c.40C>G · VCV4138646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00077%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1433	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -13.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 72 kb · p 0.00011 · regional, not allelic
Overall
CADD	22.8	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 0.00077% European (non-Finnish) · 9/1,169,454 alleles

Filtering AF 0.000362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000562% 9/1,600,766 alleles · very rare exomes 9/1,448,616 · genomes 0/152,150 · 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.Pro14Ala
Coding: c.40C>G
MANE Select: NM_001377142
Type: single nucleotide variant
Location: chr20:9307854 (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.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
PLCB4 p.Ala21Glu 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-pro14ala (accessed [today's date]).

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