Is PLCB4 p.Ser407Phe (c.1220C>T) pathogenic?

PLCB4 p.Ser407Phe (c.1220C>T) is classified Uncertain significance in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-17). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is PLCB4 p.Ser407Phe (c.1220C>T) in the general population?

PLCB4 p.Ser407Phe (c.1220C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLCB4 p.Ser407Phe (c.1220C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

PLCB4 p.Ser407Phe

c.1220C>T · VCV3637680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 2% in PLCB4
REVEL	0.683	pathogenic-leaning
SaProt	LLR -13.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLCB4
Protein: p.Ser407Phe
Coding: c.1220C>T
MANE Select: NM_001377142
Type: single nucleotide variant
Location: chr20:9389940 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 407: the pi-plc x-box domain

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

Similar variants

PLCB4 p.Ser407Tyr Uncertain significance ★ ⚠ same residue
PLCB4 p.Arg633Cys Pathogenic ★★ same type
PLCB4 p.Arg633His Pathogenic ★★ same type
PLCB4 p.Asp642Asn Pathogenic/Likely pathogenic ★★ same type
PLCB4 c.1323+8T>C Uncertain significance ★★ same type
PLCB4 c.*586C>T Uncertain significance ★★ same type
PLCB4 p.Arg640Gln Uncertain significance ★★ ⚠ same type
PLCB4 p.Glu1005Lys Uncertain significance ★★ ⚠ same type

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-ser407phe (accessed [today's date]).

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