Is PLCB4 p.Ser682= (c.2046G>A) pathogenic?

PLCB4 p.Ser682= (c.2046G>A) is classified Likely benign in PLCB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-10). Ultra-rare (popmax 0.0182%, nfe); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Ser682= (c.2046G>A)?

PLCB4 p.Ser682= (c.2046G>A) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Ser682= (c.2046G>A) in the general population?

PLCB4 p.Ser682= (c.2046G>A) is ultra-rare (popmax 0.0182%, nfe) (gnomAD).

PLCB4 p.Ser682=

c.2046G>A · rs200584230 · VCV898856

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, nfe)

Conditions

auriculocondylar syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -5
Overall
CADD	0.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0182% European (non-Finnish) · 213/1,169,430 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0159% 255/1,602,056 alleles · ultra-rare exomes 229/1,449,892 · genomes 26/152,164 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.029%	3,451
European (non-Finnish)grpmax	0.0182%	5,490
Middle Eastern	0.0165%	6,068
African / African-American	0.0161%	6,222
Admixed American	0.0117%	8,566
South Asian	0.0033%	30,261
East Asian	0.00223%	44,828

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser682=
Coding: c.2046G>A
MANE Select: NM_001377142
dbSNP: rs200584230
Type: single nucleotide variant
Location: chr20:9411083 (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

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-ser682 (accessed [today's date]).

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