Is PLCB4 p.Ala559= (c.1677G>A) pathogenic?

PLCB4 p.Ala559= (c.1677G>A) is classified Benign in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Rare (popmax 0.163%, afr); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Ala559= (c.1677G>A)?

PLCB4 p.Ala559= (c.1677G>A) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Ala559= (c.1677G>A) in the general population?

PLCB4 p.Ala559= (c.1677G>A) is rare (popmax 0.163%, afr) (gnomAD).

PLCB4 p.Ala559=

c.1677G>A · rs35479108 · VCV897692

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.163%, afr)

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 -4.3	GERP -4.5
Overall
CADD	6.953	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.163% African / African-American · 122/75,032 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.011% 177/1,613,692 alleles · rare exomes 88/1,461,386 · genomes 89/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.163%	615
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.00407%	24,577
Admixed American	0.00333%	29,995
South Asian	0.0022%	45,519
Remaining individualsnot grpmax-eligible	0.0016%	62,492

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.Ala559=
Coding: c.1677G>A
MANE Select: NM_001377142
dbSNP: rs35479108
Type: single nucleotide variant
Location: chr20:9407946 (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-ala559 (accessed [today's date]).

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