MCM4 p.Tyr522=
c.1566C>T · rs144923789 · VCV2173211
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0893%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -3.5 | GERP -4.8 |
| Overall | ||
| CADD | 6.639 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0893%
African / African-American · 67/75,024 alleles
Filtering AF
0.0721%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0659%
Overall
0.00595%
96/1,614,142 alleles · ultra-rare
exomes 54/1,461,892 · genomes 42/152,250 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0893% | 1,120 |
| East Asian | 0.0201% | 4,987 |
| Remaining individualsnot grpmax-eligible | 0.016% | 6,250 |
| Admixed American | 0.00666% | 15,006 |
| South Asian | 0.0022% | 45,535 |
| European (non-Finnish) | 0.000339% | 295,006 |
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
- MCM4
- Protein
- p.Tyr522=
- Coding
- c.1566C>T
- MANE Select
- NM_182746
- dbSNP
- rs144923789
- Type
- single nucleotide variant
- Location
- chr8:47970642 (GRCh38)
- Gene constraint
- LOEUF 0.806 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 74.25 · 28 PDB
- Residue 522
- the mcm c-terminal aaa(+) atpase domain; an α-helix
Similar variants
- MCM4 c.71-2A>G Pathogenic ★★ same type
- MCM4 c.-74C>T Uncertain significance ★★ same type
- MCM4 c.*56G>A Uncertain significance ★★ same type
- MCM4 p.Ala141Gly Uncertain significance ★★ ⚠ same type
- MCM4 p.Ala436Thr Uncertain significance ★★ ⚠ same type
- MCM4 p.Ala668Thr Uncertain significance ★★ ⚠ same type
- MCM4 p.Ala685Val Uncertain significance ★★ ⚠ same type
- MCM4 p.Ala694Thr 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/mcm4-p-tyr522 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown