Is CDCA5 p.Thr228Met (c.683C>T) pathogenic?

CDCA5 p.Thr228Met (c.683C>T) is classified Uncertain significance in CDCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely benign (0.1142); Ultra-rare (popmax 0.0113%, eas).

How common is CDCA5 p.Thr228Met (c.683C>T) in the general population?

CDCA5 p.Thr228Met (c.683C>T) is ultra-rare (popmax 0.0113%, eas) (gnomAD).

What do computational predictors say about CDCA5 p.Thr228Met (c.683C>T)?

AlphaMissense predicts likely benign (score 0.1142) — an in-silico prediction, not a clinical call.

CDCA5 p.Thr228Met

c.683C>T · rs570301807 · VCV2262166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1142	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -9.49	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 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 4,868 bp · p 0.33 · regional, not allelic
Overall
CADD	24.0	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 0.0113% East Asian · 5/44,100 alleles

Filtering AF 0.00441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0029%

Overall 0.00229% 35/1,525,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0113%	8,820
African / African-American	0.00556%	17,990
South Asian	0.00524%	19,095
Remaining individualsnot grpmax-eligible	0.00342%	29,252
European (non-Finnish)	0.00176%	56,859

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.Thr228Met
Coding: c.683C>T
MANE Select: NM_080668
dbSNP: rs570301807
Type: single nucleotide variant
Location: chr11:65079183 (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-thr228met (accessed [today's date]).

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