Is PLCE1 p.Ala2253Pro (c.6757G>C) pathogenic?

PLCE1 p.Ala2253Pro (c.6757G>C) is classified Uncertain significance in PLCE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.6374); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLCE1 p.Ala2253Pro (c.6757G>C)?

PLCE1 p.Ala2253Pro (c.6757G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PLCE1 p.Ala2253Pro (c.6757G>C) in the general population?

PLCE1 p.Ala2253Pro (c.6757G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PLCE1 p.Ala2253Pro (c.6757G>C)?

AlphaMissense predicts likely pathogenic (score 0.6374) — an in-silico prediction, not a clinical call.

PLCE1 p.Ala2253Pro

c.6757G>C · VCV3420047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6374	likely pathogenic
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 10	GERP 2.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.69 · regional, not allelic
Overall
CADD	24.5	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 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000137% 2/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
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.Ala2253Pro
Coding: c.6757G>C
MANE Select: NM_022451 · reported on NM_016341
Type: single nucleotide variant
Location: chr10:94324928 (GRCh38)

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

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-ala2253pro (accessed [today's date]).

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