Is PLCB4 p.Ser488Ala (c.1462T>G) pathogenic?

PLCB4 p.Ser488Ala (c.1462T>G) is classified Benign in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0518); Rare (popmax 0.724%, eas); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Ser488Ala (c.1462T>G)?

PLCB4 p.Ser488Ala (c.1462T>G) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Ser488Ala (c.1462T>G) in the general population?

PLCB4 p.Ser488Ala (c.1462T>G) is rare (popmax 0.724%, eas) (gnomAD).

What do computational predictors say about PLCB4 p.Ser488Ala (c.1462T>G)?

AlphaMissense predicts likely benign (score 0.0518) — an in-silico prediction, not a clinical call.

PLCB4 p.Ser488Ala

c.1462T>G · rs185740474 · VCV339563

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0518 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.724%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

auriculocondylar syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0518	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	5.488	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 0.724% East Asian · 325/44,878 alleles

Filtering AF 0.659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.634%

Overall 0.0204% 329/1,613,824 alleles · rare exomes 314/1,461,514 · genomes 15/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.724%	138
Remaining individualsnot grpmax-eligible	0.0064%	15,625

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.Ser488Ala
Coding: c.1462T>G
MANE Select: NM_001377142
dbSNP: rs185740474
Type: single nucleotide variant
Location: chr20:9395570 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 488: the 'disordered' region

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-ser488ala (accessed [today's date]).

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