Is PLCB4 p.Pro441Gln (c.1322C>A) pathogenic?

PLCB4 p.Pro441Gln (c.1322C>A) is classified Likely benign in PLCB4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-04). AlphaMissense: likely benign (0.1421); Rare (popmax 0.204%, afr).

How common is PLCB4 p.Pro441Gln (c.1322C>A) in the general population?

PLCB4 p.Pro441Gln (c.1322C>A) is rare (popmax 0.204%, afr) (gnomAD).

What do computational predictors say about PLCB4 p.Pro441Gln (c.1322C>A)?

AlphaMissense predicts likely benign (score 0.1421) — an in-silico prediction, not a clinical call.

PLCB4 p.Pro441Gln

c.1322C>A · VCV3346850

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1421 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.204%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1421	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -13.11	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	32.0	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 0.204% African / African-American · 147/71,888 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0121% 177/1,457,802 alleles · rare exomes 85/1,305,548 · genomes 92/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.204%	489
Middle Eastern	0.052%	1,925
Admixed American	0.0252%	3,975
Remaining individualsnot grpmax-eligible	0.0122%	8,172
European (non-Finnish)	0.000481%	207,689

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.Pro441Gln
Coding: c.1322C>A
MANE Select: NM_001377142
Type: single nucleotide variant
Location: chr20:9390614 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 441: the pi-plc x-box domain

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

Similar variants

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PLCB4 p.Arg633His Pathogenic ★★ same type
PLCB4 p.Asp642Asn Pathogenic/Likely pathogenic ★★ same type
PLCB4 c.1323+8T>C Uncertain significance ★★ same type
PLCB4 c.*586C>T Uncertain significance ★★ same type
PLCB4 p.Arg640Gln Uncertain significance ★★ ⚠ same type
PLCB4 p.Glu1005Lys Uncertain significance ★★ ⚠ same type
PLCB4 p.Met965Thr Uncertain significance ★★ ⚠ same type

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-pro441gln (accessed [today's date]).

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