Is PLCB4 p.Val141Ile (c.421G>A) pathogenic?

PLCB4 p.Val141Ile (c.421G>A) is classified Benign in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1156); Ultra-rare (popmax 0.0412%, nfe); Associated with auriculocondylar syndrome 2.

What condition is associated with PLCB4 p.Val141Ile (c.421G>A)?

PLCB4 p.Val141Ile (c.421G>A) is associated with auriculocondylar syndrome 2 (ClinVar).

How common is PLCB4 p.Val141Ile (c.421G>A) in the general population?

PLCB4 p.Val141Ile (c.421G>A) is ultra-rare (popmax 0.0412%, nfe) (gnomAD).

What do computational predictors say about PLCB4 p.Val141Ile (c.421G>A)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

PLCB4 p.Val141Ile

c.421G>A · rs144345083 · VCV898789

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0412%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

auriculocondylar syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.96	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 72 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.4	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 0.0412% European (non-Finnish) · 485/1,178,612 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0369%

Overall 0.0333% 537/1,612,352 alleles · ultra-rare exomes 502/1,460,186 · genomes 35/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0412%	2,430
South Asian	0.0264%	3,791
Remaining individualsnot grpmax-eligible	0.0192%	5,202
African / African-American	0.016%	6,239
Finnishnot grpmax-eligible	0.00312%	32,011
East Asian	0.00223%	44,874
Admixed American	0.00167%	59,978

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.Val141Ile
Coding: c.421G>A
MANE Select: NM_001377142
dbSNP: rs144345083
Type: single nucleotide variant
Location: chr20:9362947 (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-val141ile (accessed [today's date]).

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