Is PLCB1 p.Ser67Arg (c.199A>C) pathogenic?

PLCB1 p.Ser67Arg (c.199A>C) is classified Uncertain significance in PLCB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.8282); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with PLCB1 p.Ser67Arg (c.199A>C)?

PLCB1 p.Ser67Arg (c.199A>C) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PLCB1 p.Ser67Arg (c.199A>C) in the general population?

PLCB1 p.Ser67Arg (c.199A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PLCB1 p.Ser67Arg (c.199A>C)?

AlphaMissense predicts likely pathogenic (score 0.8282) — an in-silico prediction, not a clinical call.

PLCB1 p.Ser67Arg

c.199A>C · rs1986899325 · VCV837498

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8282	likely pathogenic
REVEL	0.192	benign-leaning
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 517 kb · p 0.00029 · regional, not allelic
Overall
CADD	24.0	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 0.00133% African / African-American · 1/74,996 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000869% 14/1,611,724 alleles · very rare exomes 14/1,459,388 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,574
Remaining individualsnot grpmax-eligible	0.0016%	62,426
African / African-Americangrpmax	0.00133%	74,996
European (non-Finnish)	0.000934%	107,081

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PLCB1
Protein: p.Ser67Arg
Coding: c.199A>C
MANE Select: NM_015192
dbSNP: rs1986899325
Type: single nucleotide variant
Location: chr20:8371403 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.55

Full PLCB1 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

Also linked: developmental and epileptic encephalopathy, 12

Similar variants

PLCB1 p.Ser67Asn Uncertain significance ★ ⚠ same residue
PLCB1 p.Ser67Thr Uncertain significance ★ ⚠ same residue
PLCB1 p.Arg222Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 p.Arg815Ter Pathogenic/Likely pathogenic ★★ same condition
PLCB1 c.3336+3A>G Uncertain significance ★★ same condition
PLCB1 p.Ala1046Ser Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1046Thr Uncertain significance ★★ ⚠ same condition
PLCB1 p.Ala1116Val 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/plcb1-p-ser67arg (accessed [today's date]).

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