Is CDCA7 p.Arg257Cys (c.769C>T) pathogenic?

CDCA7 p.Arg257Cys (c.769C>T) is classified Uncertain significance in CDCA7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-28). AlphaMissense: ambiguous (0.4068); Ultra-rare (popmax 0.0219%, amr).

How common is CDCA7 p.Arg257Cys (c.769C>T) in the general population?

CDCA7 p.Arg257Cys (c.769C>T) is ultra-rare (popmax 0.0219%, amr) (gnomAD).

What do computational predictors say about CDCA7 p.Arg257Cys (c.769C>T)?

AlphaMissense predicts ambiguous (score 0.4068) — an in-silico prediction, not a clinical call.

CDCA7 p.Arg257Cys

c.769C>T · rs147594902 · VCV1046757

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, amr)

Computational evidence

Protein change
AlphaMissense	0.4068	ambiguous
REVEL	0.323	indeterminate
SaProt	LLR -7.16	tolerated
Splicing
SpliceAI	Δ0.46	acceptor gain · deltas
Pangolin	Δ0.44	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.02 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R178C vs ClinVar R257C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0219% Admixed American · 13/59,248 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.0121% 195/1,610,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0219%	4,558
Remaining individualsnot grpmax-eligible	0.0176%	5,669
European (non-Finnish)	0.0139%	7,189
Finnishnot grpmax-eligible	0.00625%	16,001
South Asian	0.00332%	30,146

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: CDCA7
Protein: p.Arg257Cys
Coding: c.769C>T
MANE Select: NM_031942
dbSNP: rs147594902
Type: single nucleotide variant
Location: chr2:173364864 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.93 · 2 PDB
Residue 257: an α-helix

Full CDCA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDCA7 c.384+2T>C Uncertain significance ★★ same type
CDCA7 p.Ala157Val Uncertain significance ★★ ⚠ same type
CDCA7 p.Ala391Gly Uncertain significance ★★ ⚠ same type
CDCA7 p.Arg134Leu Uncertain significance ★★ ⚠ same type
CDCA7 p.Arg134Trp Uncertain significance ★★ ⚠ same type
CDCA7 p.Arg171Cys Uncertain significance ★★ ⚠ same type
CDCA7 p.Arg171Leu Uncertain significance ★★ ⚠ same type
CDCA7 p.Arg239Gln 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/cdca7-p-arg257cys (accessed [today's date]).

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