Is CENPC p.Ser447Leu (c.1340C>T) pathogenic?

CENPC p.Ser447Leu (c.1340C>T) is classified Uncertain significance in CENPC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-21). AlphaMissense: likely benign (0.0971); Very rare (popmax 0.00856%, nfe).

How common is CENPC p.Ser447Leu (c.1340C>T) in the general population?

CENPC p.Ser447Leu (c.1340C>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about CENPC p.Ser447Leu (c.1340C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

CENPC p.Ser447Leu

c.1340C>T · rs374045875 · VCV2361080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.37	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 3.1	GERP -0.44, phastCons 0.88
Regional constraint	o/e 0.91	unconstrained · MANE · 73 kb · p 0.0018 · regional, not allelic
Overall
CADD	18.51	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 0.00856% European (non-Finnish) · 101/1,179,416 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00645% 104/1,612,466 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00856%	11,677
Remaining individualsnot grpmax-eligible	0.0016%	62,404
Finnishnot grpmax-eligible	0.00157%	63,668
African / African-American	0.00134%	74,886

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: CENPC
Protein: p.Ser447Leu
Coding: c.1340C>T
MANE Select: NM_001812
dbSNP: rs374045875
Type: single nucleotide variant
Location: chr4:67514178 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.33 · 17 PDB
Residue 447: the 'disordered' region

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

Similar variants

CENPC p.Ala165Thr Uncertain significance ★ ⚠ same type
CENPC p.Ala23Val Uncertain significance ★ ⚠ same type
CENPC p.Ala313Val Uncertain significance ★ ⚠ same type
CENPC p.Ala324Thr Uncertain significance ★ ⚠ same type
CENPC p.Ala783Glu Uncertain significance ★ ⚠ same type
CENPC p.Ala783Thr Uncertain significance ★ ⚠ same type
CENPC p.Arg24His Uncertain significance ★ ⚠ same type
CENPC p.Arg272Gln 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/cenpc-p-ser447leu (accessed [today's date]).

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