Is PLCB4 p.Asp278Val (c.833A>T) pathogenic?

PLCB4 p.Asp278Val (c.833A>T) is classified Conflicting classifications of pathogenicity in PLCB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-18). AlphaMissense: likely benign (0.0987); Rare (popmax 0.359%, afr); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Asp278Val (c.833A>T)?

PLCB4 p.Asp278Val (c.833A>T) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Asp278Val (c.833A>T) in the general population?

PLCB4 p.Asp278Val (c.833A>T) is rare (popmax 0.359%, afr) (gnomAD).

What do computational predictors say about PLCB4 p.Asp278Val (c.833A>T)?

AlphaMissense predicts likely benign (score 0.0987) — an in-silico prediction, not a clinical call.

PLCB4 p.Asp278Val

c.833A>T · rs147655952 · VCV339557

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0987 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.359%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

auriculocondylar syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0987	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 4,106 bp · p 0.11 · regional, not allelic
Overall
CADD	23.4	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 0.359% African / African-American · 260/72,356 alleles

Filtering AF 0.323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.309%

Overall 0.0218% 334/1,530,984 alleles · rare exomes 177/1,378,880 · genomes 157/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.359%	278
Remaining individualsnot grpmax-eligible	0.0471%	2,123
Admixed American	0.0397%	2,520
South Asian	0.00248%	40,376
European (non-Finnish)	0.00205%	48,852

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.Asp278Val
Coding: c.833A>T
MANE Select: NM_001377142
dbSNP: rs147655952
Type: single nucleotide variant
Location: chr20:9380142 (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-asp278val (accessed [today's date]).

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