Is PLCE1 p.Pro847Ala (c.2539C>G) pathogenic?

PLCE1 p.Pro847Ala (c.2539C>G) is classified Uncertain significance in PLCE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-16). AlphaMissense: likely pathogenic (0.7874); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLCE1 p.Pro847Ala (c.2539C>G)?

PLCE1 p.Pro847Ala (c.2539C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLCE1 p.Pro847Ala (c.2539C>G) in the general population?

PLCE1 p.Pro847Ala (c.2539C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PLCE1 p.Pro847Ala (c.2539C>G)?

AlphaMissense predicts likely pathogenic (score 0.7874) — an in-silico prediction, not a clinical call.

PLCE1 p.Pro847Ala

c.2539C>G · rs2050668187 · VCV1311915

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7874 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7874	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -3.51	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 214 kb · p 0.44 · regional, not allelic
Overall
CADD	23.3	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,614,142 alleles · ultra-rare exomes 6/1,461,860 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00267%	37,522
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,074
European (non-Finnish)	8.47e-05%	1,180,013

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: PLCE1
Protein: p.Pro847Ala
Coding: c.2539C>G
MANE Select: NM_016341
dbSNP: rs2050668187
Type: single nucleotide variant
Location: chr10:94246064 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.01 · 3 PDB

Full PLCE1 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

PLCE1 c.4917+3G>A Uncertain significance ★★ same condition
PLCE1 p.Arg1057Gln Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg1116Gln Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg1118Gln Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg1147Gly Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg693Cys Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg729Gln Uncertain significance ★★ ⚠ same condition
PLCE1 p.Arg775Trp 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/plce1-p-pro847ala (accessed [today's date]).

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