Is CDCA8 p.Arg166Cys (c.496C>T) pathogenic?

CDCA8 p.Arg166Cys (c.496C>T) is classified Uncertain significance in CDCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.0795); Very rare (popmax 0.00267%, afr).

How common is CDCA8 p.Arg166Cys (c.496C>T) in the general population?

CDCA8 p.Arg166Cys (c.496C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CDCA8 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

CDCA8 p.Arg166Cys

c.496C>T · rs374879708 · VCV3141035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -9.21	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 1.6	GERP -1.3, phastCons 0.83
Regional constraint	o/e 0.80	unconstrained · MANE · 16 kb · p 0.00025 · regional, not allelic
Overall
CADD	20.3	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 0.00267% African / African-American · 2/74,896 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,004 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,448
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)	0.000254%	393,184

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: CDCA8
Protein: p.Arg166Cys
Coding: c.496C>T
MANE Select: NM_001256875
dbSNP: rs374879708
Type: single nucleotide variant
Location: chr1:37703259 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.28 · 15 PDB
Residue 166: the 'disordered' region

Full CDCA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDCA8 p.Arg166His Likely benign ★ ⚠ same residue
CDCA8 p.Ala140Val Uncertain significance ★ ⚠ same type
CDCA8 p.Ala173Val Uncertain significance ★ ⚠ same type
CDCA8 p.Arg176Gln Uncertain significance ★ ⚠ same type
CDCA8 p.Arg210Trp Uncertain significance ★ ⚠ same type
CDCA8 p.Arg240Gln Uncertain significance ★ ⚠ same type
CDCA8 p.Arg277Gln Uncertain significance ★ ⚠ same type
CDCA8 p.Arg35Gln 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/cdca8-p-arg166cys (accessed [today's date]).

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