Is CENPE p.Pro2222Ala (c.6664C>G) pathogenic?

CENPE p.Pro2222Ala (c.6664C>G) is classified Uncertain significance in CENPE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0928); Absent from gnomAD v4.1.

How common is CENPE p.Pro2222Ala (c.6664C>G) in the general population?

CENPE p.Pro2222Ala (c.6664C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CENPE p.Pro2222Ala (c.6664C>G)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

CENPE p.Pro2222Ala

c.6664C>G · rs554214225 · VCV2249889

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.189	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.097, phastCons 0.35
Regional constraint	o/e 0.97	unconstrained · MANE · 71 kb · p 0.13 · regional, not allelic
Overall
CADD	16.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: CENPE
Protein: p.Pro2222Ala
Coding: c.6664C>G
MANE Select: NM_001813
dbSNP: rs554214225
Type: single nucleotide variant
Location: chr4:103133751 (GRCh38)
Gene constraint: LOEUF 0.451 · pLI 1.00 (gnomAD)
Residue 2222: the 'kinetochore-binding domain' region

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

Similar variants

CENPE p.Arg2279Cys Uncertain significance ★★ ⚠ same type
CENPE p.Arg760Ser Uncertain significance ★★ ⚠ same type
CENPE p.Asn1145Lys Uncertain significance ★★ ⚠ same type
CENPE p.Asn1165Ser Uncertain significance ★★ ⚠ same type
CENPE p.Asp1960Tyr Uncertain significance ★★ ⚠ same type
CENPE p.Asp954Asn Uncertain significance ★★ same type
CENPE p.Asp954Tyr Uncertain significance ★★ same type
CENPE p.Gln2022Glu 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/cenpe-p-pro2222ala (accessed [today's date]).

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