Is CDC16 p.Pro399Ala (c.1195C>G) pathogenic?

CDC16 p.Pro399Ala (c.1195C>G) is classified Uncertain significance in CDC16 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: ambiguous (0.5542); Very rare (popmax 0.00246%, nfe).

How common is CDC16 p.Pro399Ala (c.1195C>G) in the general population?

CDC16 p.Pro399Ala (c.1195C>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about CDC16 p.Pro399Ala (c.1195C>G)?

AlphaMissense predicts ambiguous (score 0.5542) — an in-silico prediction, not a clinical call.

CDC16 p.Pro399Ala

c.1195C>G · rs760691458 · VCV3140777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5542	ambiguous
REVEL	0.377	indeterminate
SaProt	LLR -10.93	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 37 kb · p 0.00031 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,179,488 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,613,248 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,672
Finnishnot grpmax-eligible	0.00156%	63,988

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: CDC16
Protein: p.Pro399Ala
Coding: c.1195C>G
MANE Select: NM_001078645
dbSNP: rs760691458
Type: single nucleotide variant
Location: chr13:114257175 (GRCh38)
Gene constraint: LOEUF 0.657 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 21 PDB

Full CDC16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC16 p.Pro399Leu Uncertain significance ★ ⚠ same residue
CDC16 p.Ile132= Benign ★★ same type
CDC16 p.Ala142Thr Uncertain significance ★ ⚠ same type
CDC16 p.Ala319Thr Uncertain significance ★ ⚠ same type
CDC16 p.Ala44Gly Uncertain significance ★ ⚠ same type
CDC16 p.Ala479Ser Uncertain significance ★ ⚠ same type
CDC16 p.Ala51Thr Uncertain significance ★ ⚠ same type
CDC16 p.Ala536Ser 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/cdc16-p-pro399ala (accessed [today's date]).

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