Is CDCA8 p.Leu21Phe (c.61C>T) pathogenic?

CDCA8 p.Leu21Phe (c.61C>T) is classified Uncertain significance in CDCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: ambiguous (0.3808); Very rare (popmax 0.00551%, nfe).

How common is CDCA8 p.Leu21Phe (c.61C>T) in the general population?

CDCA8 p.Leu21Phe (c.61C>T) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about CDCA8 p.Leu21Phe (c.61C>T)?

AlphaMissense predicts ambiguous (score 0.3808) — an in-silico prediction, not a clinical call.

CDCA8 p.Leu21Phe

c.61C>T · rs771828918 · VCV2288672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3808	ambiguous
REVEL	0.285	benign-leaning
SaProt	LLR -8.60	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 5.9	GERP 0.94, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 16 kb · p 0.00025 · regional, not allelic
Overall
CADD	26.6	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 0.00551% European (non-Finnish) · 65/1,179,978 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00403% 65/1,613,436 alleles · very rare

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.Leu21Phe
Coding: c.61C>T
MANE Select: NM_001256875
dbSNP: rs771828918
Type: single nucleotide variant
Location: chr1:37692751 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.28 · 15 PDB
Residue 21: the 'required for interaction with senp3' region; the 'required for centromere localization' region; the 'required for interaction with incenp' region; the 'required to form a minimal cpc core complex that localizes to the central spindle and midbody and properly executes the role of the cpc during cytokinesis' region; an α-helix; the 'required for interaction with incenp and birc5' region

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

Similar variants

CDCA8 p.Ala140Val Uncertain significance ★ ⚠ same type
CDCA8 p.Ala173Val Uncertain significance ★ ⚠ same type
CDCA8 p.Arg166Cys 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-leu21phe (accessed [today's date]).

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