Is CDCA7 p.Pro244Leu (c.731C>T) pathogenic?

CDCA7 p.Pro244Leu (c.731C>T) is classified Uncertain significance in CDCA7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-25). AlphaMissense: likely benign (0.1128); Ultra-rare (popmax 0.0498%, mid); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 3.

What condition is associated with CDCA7 p.Pro244Leu (c.731C>T)?

CDCA7 p.Pro244Leu (c.731C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 3 (ClinVar).

How common is CDCA7 p.Pro244Leu (c.731C>T) in the general population?

CDCA7 p.Pro244Leu (c.731C>T) is ultra-rare (popmax 0.0498%, mid) (gnomAD).

What do computational predictors say about CDCA7 p.Pro244Leu (c.731C>T)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

CDCA7 p.Pro244Leu

c.731C>T · rs770948684 · VCV964462

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0498%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.86	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 2.3	GERP 0.84, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.02 · regional, not allelic
Overall
CADD	22.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P165L vs ClinVar P244L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0498% Middle Eastern · 3/6,028 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00224% 36/1,610,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0498%	2,009
African / African-American	0.0241%	4,147
Remaining individualsnot grpmax-eligible	0.0112%	8,908
Admixed American	0.00169%	59,284
European (non-Finnish)	0.000594%	168,399

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.Pro244Leu
Coding: c.731C>T
MANE Select: NM_031942
dbSNP: rs770948684
Type: single nucleotide variant
Location: chr2:173364826 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.93 · 2 PDB
Residue 244: an α-helix

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

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDCA7 p.Pro244= Uncertain significance ★ same residue
CDCA7 p.Ala391Gly Uncertain significance ★★ ⚠ same condition
CDCA7 c.22-17G>T Benign ★★ same condition
CDCA7 c.622-128C>T Benign ★★ same condition
CDCA7 c.895-27C>G Benign ★★ same condition
CDCA7 p.Asn331= Likely benign ★★ same condition
CDCA7 p.Thr359= Benign ★★ same condition
CDCA7 p.Arg353Cys Likely pathogenic ★ same condition

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-pro244leu (accessed [today's date]).

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