Is CDCA5 p.Pro223Ser (c.667C>T) pathogenic?

CDCA5 p.Pro223Ser (c.667C>T) is classified Uncertain significance in CDCA5 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.3804); Ultra-rare (popmax 0.0278%, nfe).

How common is CDCA5 p.Pro223Ser (c.667C>T) in the general population?

CDCA5 p.Pro223Ser (c.667C>T) is ultra-rare (popmax 0.0278%, nfe) (gnomAD).

What do computational predictors say about CDCA5 p.Pro223Ser (c.667C>T)?

AlphaMissense predicts ambiguous (score 0.3804) — an in-silico prediction, not a clinical call.

CDCA5 p.Pro223Ser

c.667C>T · rs200209838 · VCV2551868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0278%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3804	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.80	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 4,868 bp · p 0.33 · regional, not allelic
Overall
CADD	24.1	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 0.0278% European (non-Finnish) · 328/1,180,000 alleles

Filtering AF 0.0253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0243%

Overall 0.0208% 335/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0278%	3,598
Remaining individualsnot grpmax-eligible	0.0064%	15,628
African / African-American	0.00267%	37,493
Finnishnot grpmax-eligible	0.00156%	64,026

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: CDCA5
Protein: p.Pro223Ser
Coding: c.667C>T
MANE Select: NM_080668
dbSNP: rs200209838
Type: single nucleotide variant
Location: chr11:65079364 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.04

Full CDCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDCA5 p.Glu123Lys Benign ★★ same type
CDCA5 p.Gly173= Benign ★★ same type
CDCA5 p.Gly179Arg Benign ★★ same type
CDCA5 p.Pro120= Benign ★★ same type
CDCA5 p.Thr105= Benign ★★ same type
CDCA5 p.Ala51Thr Uncertain significance ★ ⚠ same type
CDCA5 p.Arg148Trp Uncertain significance ★ same type
CDCA5 p.Arg4Gly 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/cdca5-p-pro223ser (accessed [today's date]).

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