MMACHC p.Pro248=
c.744G>A · VCV4972672
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
rare (popmax 0.182%, mid)
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 -3.5 | GERP -3.5 |
| Overall | ||
| CADD | 0.845 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.182%
Middle Eastern · 11/6,052 alleles
Filtering AF
0.102%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0788%
Overall
0.00285%
46/1,612,140 alleles · rare
exomes 42/1,460,128 · genomes 4/152,012 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.182% | 550 |
| Admixed American | 0.00335% | 29,893 |
| European (non-Finnish) | 0.00246% | 40,660 |
| East Asian | 0.00223% | 44,866 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,400 |
| Finnishnot grpmax-eligible | 0.00157% | 63,878 |
| African / African-American | 0.00134% | 74,874 |
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
- MMACHC
- Protein
- p.Pro248=
- Coding
- c.744G>A
- MANE Select
- NM_015506
- Type
- single nucleotide variant
- Location
- chr1:45509110 (GRCh38)
- Gene constraint
- LOEUF 1.162 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 86.41 · 7 PDB
- Residue 248
- the 'disordered' region
Similar variants
- MMACHC p.Pro248Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
- MMACHC p.Pro248Leu Uncertain significance ★ ⚠ same residue
- MMACHC c.430-1G>A Likely pathogenic ★★ same type
- MMACHC c.430-2A>G Likely pathogenic ★★ same type
- MMACHC c.81+1G>A Pathogenic ★★ same type
- MMACHC c.81+1G>C Pathogenic/Likely pathogenic ★★ same type
- MMACHC c.81+2T>G Pathogenic/Likely pathogenic ★★ same type
- MMACHC c.82-1G>A Pathogenic/Likely 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/mmachc-p-pro248 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown