Is PLCB4 p.Asn599Ser (c.1796A>G) pathogenic?

PLCB4 p.Asn599Ser (c.1796A>G) is classified Uncertain significance in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-15). AlphaMissense: likely benign (0.2106); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLCB4 p.Asn599Ser (c.1796A>G)?

PLCB4 p.Asn599Ser (c.1796A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLCB4 p.Asn599Ser (c.1796A>G) in the general population?

PLCB4 p.Asn599Ser (c.1796A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about PLCB4 p.Asn599Ser (c.1796A>G)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

PLCB4 p.Asn599Ser

c.1796A>G · VCV3933680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -10.47	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM N587S vs ClinVar N599S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,834 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000519% 8/1,542,008 alleles · very rare exomes 6/1,389,798 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,917
Remaining individualsnot grpmax-eligible	0.00333%	29,985
European (non-Finnish)	0.000359%	278,775

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.Asn599Ser
Coding: c.1796A>G
MANE Select: NM_001377142
Type: single nucleotide variant
Location: chr20:9408639 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 587 UniProt numbering: the pi-plc y-box domain

Full PLCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLCB4 p.Arg633His Pathogenic ★★ same condition
PLCB4 p.Arg640Gln Uncertain significance ★★ ⚠ same condition
PLCB4 p.Glu1005Lys Uncertain significance ★★ ⚠ same condition
PLCB4 p.Thr1016Met Uncertain significance ★★ ⚠ same condition
PLCB4 p.Val763Ile Uncertain significance ★★ ⚠ same condition
PLCB4 p.Ala1102Thr Uncertain significance ★ ⚠ same condition
PLCB4 p.Ala1102Val Uncertain significance ★ ⚠ same condition
PLCB4 p.Ala21Glu Uncertain significance ★ ⚠ 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-asn599ser (accessed [today's date]).

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