Is AURKC p.Leu74Pro (c.221T>C) pathogenic?

AURKC p.Leu74Pro (c.221T>C) is classified Uncertain significance in AURKC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely pathogenic (0.9938); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AURKC p.Leu74Pro (c.221T>C)?

AURKC p.Leu74Pro (c.221T>C) is associated with Inborn genetic diseases (ClinVar).

How common is AURKC p.Leu74Pro (c.221T>C) in the general population?

AURKC p.Leu74Pro (c.221T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AURKC p.Leu74Pro (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

AURKC p.Leu74Pro

c.221T>C · rs768463930 · VCV2314293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic · top 6% in AURKC
REVEL	0.467	indeterminate
SaProt	LLR -16.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.9, phastCons 0.32
Regional constraint	o/e 0.87	unconstrained · MANE · 4,165 bp · p 0.0089 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: AURKC
Protein: p.Leu74Pro
Coding: c.221T>C
MANE Select: NM_001015878
dbSNP: rs768463930
Type: single nucleotide variant
Location: chr19:57232149 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.25 · 3 PDB
Residue 74: the protein kinase domain; a β-strand

Full AURKC 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

Similar variants

AURKC p.Ala113Val Uncertain significance ★ ⚠ same condition
AURKC p.Arg114His Uncertain significance ★ ⚠ same condition
AURKC p.Arg115Trp Uncertain significance ★ ⚠ same condition
AURKC p.Arg142Cys Uncertain significance ★ ⚠ same condition
AURKC p.Arg250His Uncertain significance ★ ⚠ same condition
AURKC p.Arg299Lys Uncertain significance ★ ⚠ same condition
AURKC p.Arg5Gly Uncertain significance ★ ⚠ same condition
AURKC p.Asn24Lys Uncertain significance ★ ⚠ same condition

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/aurkc-p-leu74pro (accessed [today's date]).

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