Is CENPL p.Pro134Leu (c.401C>T) pathogenic?

CENPL p.Pro134Leu (c.401C>T) is classified Uncertain significance in CENPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.1255); Ultra-rare (popmax 0.0166%, mid).

How common is CENPL p.Pro134Leu (c.401C>T) in the general population?

CENPL p.Pro134Leu (c.401C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about CENPL p.Pro134Leu (c.401C>T)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

CENPL p.Pro134Leu

c.401C>T · VCV4652138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.099 · regional, not allelic
Overall
CADD	23.2	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

Grpmax group 0.0166% Middle Eastern · 1/6,038 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000622% 10/1,607,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,038
Admixed American	0.00168%	59,512
European (non-Finnish)	0.000681%	146,949

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: CENPL
Protein: p.Pro134Leu
Coding: c.401C>T
MANE Select: NM_001387287
Type: single nucleotide variant
Location: chr1:173807286 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 83.44 · 12 PDB
Residue 134: an α-helix

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

Similar variants

CENPL p.Ala108Val Uncertain significance ★ ⚠ same type
CENPL p.Ala212Gly Uncertain significance ★ ⚠ same type
CENPL p.Ala227Thr Uncertain significance ★ ⚠ same type
CENPL p.Ala255Thr Uncertain significance ★ ⚠ same type
CENPL p.Arg16Ile Uncertain significance ★ ⚠ same type
CENPL p.Arg30Gln Uncertain significance ★ ⚠ same type
CENPL p.Arg30Pro Uncertain significance ★ ⚠ same type
CENPL p.Asn187Lys 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/cenpl-p-pro134leu (accessed [today's date]).

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