MCPH1 p.His99=
c.297C>T · rs727504012 · VCV167281
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 5 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0501%, amr)
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 -0.52 | GERP -4.6 |
| Overall | ||
| CADD | 0.583 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0501%
Admixed American · 30/59,914 alleles
Filtering AF
0.036%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0313%
Overall
0.00571%
92/1,611,330 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0501% | 1,997 |
| Remaining individualsnot grpmax-eligible | 0.00802% | 12,476 |
| East Asian | 0.0067% | 14,927 |
| European (non-Finnish) | 0.0045% | 22,234 |
| African / African-American | 0.00134% | 74,756 |
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
- MCPH1
- Protein
- p.His99=
- Coding
- c.297C>T
- MANE Select
- NM_024596
- dbSNP
- rs727504012
- Type
- single nucleotide variant
- Location
- chr8:6431562 (GRCh38)
- Gene constraint
- LOEUF 1.342 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 59.80 · 9 PDB
- Residue 99
- a turn
Similar variants
- MCPH1 c.321+2T>C Likely pathogenic ★★ same type
- MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
- MCPH1 p.Gln199Ter Pathogenic ★★ same type
- MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same type
- MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same type
- MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same type
- MCPH1 p.Lys105Ter Pathogenic/Likely pathogenic ★★ same type
- MCPH1 p.Ser233Ter Pathogenic ★★ 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/mcph1-p-his99 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown