Is PLCB4 p.Ser341Thr (c.1021T>A) pathogenic?

PLCB4 p.Ser341Thr (c.1021T>A) is classified Uncertain significance in PLCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-16). AlphaMissense: likely pathogenic (0.9627); Very rare (popmax 0.00333%, amr).

How common is PLCB4 p.Ser341Thr (c.1021T>A) in the general population?

PLCB4 p.Ser341Thr (c.1021T>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PLCB4 p.Ser341Thr (c.1021T>A)?

AlphaMissense predicts likely pathogenic (score 0.9627) — an in-silico prediction, not a clinical call.

PLCB4 p.Ser341Thr

c.1021T>A · VCV4886180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9627	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -13.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 4.1e-14 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,614,076 alleles · very rare exomes 3/1,461,870 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,005
European (non-Finnish)	0.000169%	590,016

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.Ser341Thr
Coding: c.1021T>A
MANE Select: NM_001377142
Type: single nucleotide variant
Location: chr20:9384368 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 86.03
Residue 341: the pi-plc x-box domain

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

Similar variants

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
PLCB4 p.Met965Thr 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-ser341thr (accessed [today's date]).

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