GCM2 p.Pro433=
c.1299G>A · rs527620122 · VCV2146946
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00533%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.3 | GERP -0.69 |
| Overall | ||
| CADD | 2.86 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00533%
African / African-American · 4/75,062 alleles
Filtering AF
0.00174%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00116%
Overall
0.00217%
35/1,614,184 alleles · very rare
exomes 25/1,461,860 · genomes 10/152,324 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00533% | 18,765 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,255 |
| East Asian | 0.00223% | 44,878 |
| South Asian | 0.0022% | 45,545 |
| European (non-Finnish) | 0.00203% | 49,167 |
| Admixed American | 0.00167% | 60,014 |
| Finnishnot grpmax-eligible | 0.00156% | 64,038 |
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
- GCM2
- Protein
- p.Pro433=
- Coding
- c.1299G>A
- MANE Select
- NM_004752
- dbSNP
- rs527620122
- Type
- single nucleotide variant
- Location
- chr6:10874217 (GRCh38)
- Gene constraint
- LOEUF 1.205 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 58.78
- Residue 433
- a UniProt-annotated variant site (in fih2; transcription of mrna, but loss of protein expression)
Similar variants
- GCM2 p.Pro433Leu Likely benign ★★ same residue
- GCM2 c.90+2T>G Likely pathogenic ★★ same type
- GCM2 p.Arg47Leu Pathogenic ★★ same type
- GCM2 p.Arg67Cys Likely pathogenic ★★ same type
- GCM2 p.Tyr136Ter Pathogenic ★★ same type
- GCM2 c.*217T>A Uncertain significance ★★ same type
- GCM2 p.Ala148Val Uncertain significance ★★ ⚠ same type
- GCM2 p.Ala180Pro 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/gcm2-p-pro433 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown