MCPH1 p.Ala757=
c.2271C>T · rs371576977 · VCV2960396
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.016%, 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 -7 | GERP -4.1 |
| Overall | ||
| CADD | 1.23 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.016%
African / African-American · 12/74,928 alleles
Filtering AF
0.00921%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00722%
Overall
0.00186%
30/1,614,024 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.016% | 6,244 |
| South Asian | 0.00549% | 18,217 |
| East Asian | 0.00223% | 44,894 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,482 |
| European (non-Finnish) | 0.000932% | 107,276 |
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.Ala757=
- Coding
- c.2271C>T
- MANE Select
- NM_024596
- dbSNP
- rs371576977
- Type
- single nucleotide variant
- Location
- chr8:6621510 (GRCh38)
- Gene constraint
- LOEUF 1.342 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 59.80 · 9 PDB
- Residue 757
- the brct 3 domain; 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-ala757 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown