Is PLCB4 p.Pro777= (c.2331G>C) pathogenic?

PLCB4 p.Pro777= (c.2331G>C) is classified Benign/Likely benign in PLCB4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-31). Rare (popmax 0.13%, sas); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Pro777= (c.2331G>C)?

PLCB4 p.Pro777= (c.2331G>C) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Pro777= (c.2331G>C) in the general population?

PLCB4 p.Pro777= (c.2331G>C) is rare (popmax 0.13%, sas) (gnomAD).

PLCB4 p.Pro777=

c.2331G>C · rs147575829 · VCV339576

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.13%, sas)

Conditions

auriculocondylar syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -4.7
Overall
CADD	0.018	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.13% South Asian · 118/90,974 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.0635% 1,025/1,613,514 alleles · rare exomes 973/1,461,204 · genomes 52/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.13%	771
Remaining individualsnot grpmax-eligible	0.0752%	1,329
European (non-Finnish)	0.0699%	1,430
Admixed American	0.0417%	2,398
Middle Eastern	0.0165%	6,058
African / African-American	0.0107%	9,379
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592

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.Pro777=
Coding: c.2331G>C
MANE Select: NM_001377142
dbSNP: rs147575829
Type: single nucleotide variant
Location: chr20:9423759 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 777: the c2 domain

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

Disease context

auriculocondylar syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCB4 p.Arg633Cys Pathogenic ★★ same condition
PLCB4 p.Arg633His Pathogenic ★★ same condition
PLCB4 p.Asp642Asn Pathogenic/Likely pathogenic ★★ same condition
PLCB4 c.1323+8T>C Uncertain significance ★★ same condition
PLCB4 c.*586C>T Uncertain significance ★★ same condition
PLCB4 p.Met965Thr Uncertain significance ★★ ⚠ same condition
PLCB4 c.1065-8A>G Benign ★★ same condition
PLCB4 c.1611+12C>T Likely benign ★★ 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-pro777 (accessed [today's date]).

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