Is CDCA2 p.Arg996Trp (c.2986C>T) pathogenic?

CDCA2 p.Arg996Trp (c.2986C>T) is classified Uncertain significance in CDCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.1761); Ultra-rare (popmax 0.0657%, mid).

How common is CDCA2 p.Arg996Trp (c.2986C>T) in the general population?

CDCA2 p.Arg996Trp (c.2986C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about CDCA2 p.Arg996Trp (c.2986C>T)?

AlphaMissense predicts likely benign (score 0.1761) — an in-silico prediction, not a clinical call.

CDCA2 p.Arg996Trp

c.2986C>T · VCV4223497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1761	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -9.86	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 -0.53	GERP -4.8
Regional constraint	o/e 1.04	unconstrained · MANE · 47 kb · p 0.15 · regional, not allelic
Overall
CADD	14.21	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00397% 64/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
Admixed American	0.0217%	4,616
South Asian	0.0165%	6,073
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00246%	40,691

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: CDCA2
Protein: p.Arg996Trp
Coding: c.2986C>T
MANE Select: NM_152562
Type: single nucleotide variant
Location: chr8:25507652 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 46.61 · 4 PDB
Residue 996: the 'disordered' region

Full CDCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDCA2 p.Arg996Gln Uncertain significance ★ ⚠ same residue
CDCA2 p.Val467Ile Uncertain significance ★★ ⚠ same type
CDCA2 p.Lys754Thr Benign ★★ same type
CDCA2 p.Ser291= Benign ★★ same type
CDCA2 p.Thr50Ile Benign ★★ same type
CDCA2 p.Ala187Thr Uncertain significance ★ ⚠ same type
CDCA2 p.Ala217Val Uncertain significance ★ ⚠ same type
CDCA2 p.Ala23Val 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/cdca2-p-arg996trp (accessed [today's date]).

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