Is CENPE p.Arg459Ter (c.1375C>T) pathogenic?

CENPE p.Arg459Ter (c.1375C>T) is classified Uncertain significance in CENPE (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-09). Very rare (popmax 0.00187%, amr).

How common is CENPE p.Arg459Ter (c.1375C>T) in the general population?

CENPE p.Arg459Ter (c.1375C>T) is very rare (popmax 0.00187%, amr) (gnomAD).

CENPE p.Arg459Ter

c.1375C>T · VCV3365794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 14 of 49
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.34	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.6	GERP 1.4, phastCons 0.8
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% Admixed American · 1/53,436 alleles

Filtering AF 0.000252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000162%

Overall 0.000565% 8/1,414,922 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00187%	53,436
European (non-Finnish)	0.000606%	164,959

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: CENPE
Protein: p.Arg459Ter
Coding: c.1375C>T
MANE Select: NM_001813
Type: single nucleotide variant
Location: chr4:103176914 (GRCh38)
Gene constraint: LOEUF 0.451 · pLI 1.00 (gnomAD)

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

Similar variants

CENPE p.Arg459Gln Uncertain significance ★ ⚠ same residue
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

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-arg459ter (accessed [today's date]).

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