MADD p.Pro258=
c.774A>G · rs74698331 · VCV2433594
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.136%, nfe)
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 -5.3 | GERP -4.4 |
| Overall | ||
| CADD | 5.551 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.136%
European (non-Finnish) · 1,602/1,180,030 alleles
Filtering AF
0.13%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.128%
Overall
0.111%
1,789/1,614,190 alleles · rare
exomes 1,652/1,461,894 · genomes 137/152,296 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.136% | 737 |
| Admixed American | 0.123% | 811 |
| Remaining individualsnot grpmax-eligible | 0.117% | 856 |
| Middle Eastern | 0.066% | 1,516 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0574% | 1,742 |
| African / African-American | 0.0187% | 5,360 |
| Finnishnot grpmax-eligible | 0.00468% | 21,347 |
| South Asian | 0.0022% | 45,541 |
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
- MADD
- Protein
- p.Pro258=
- Coding
- c.774A>G
- MANE Select
- NM_001376571
- dbSNP
- rs74698331
- Type
- single nucleotide variant
- Location
- chr11:47276013 (GRCh38)
- Gene constraint
- LOEUF 0.725 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 64.59
- Residue 258
- the udenn domain; a UniProt-annotated variant site (in deeah; uncertain significance)
Similar variants
- MADD c.2816+1G>A Pathogenic ★★ same type
- MADD p.Arg1532Ter Pathogenic ★★ same type
- MADD p.Arg327Ter Pathogenic/Likely pathogenic ★★ same type
- MADD p.Ala1029Val Uncertain significance ★★ ⚠ same type
- MADD p.Ala165Val Uncertain significance ★★ ⚠ same type
- MADD p.Arg1077Gly Uncertain significance ★★ ⚠ same type
- MADD p.Arg1273His Uncertain significance ★★ ⚠ same type
- MADD p.Arg170His 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/madd-p-pro258 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown