MADD p.Pro1538=
c.4614C>T · VCV4873778
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.099%, 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 -15 | GERP -3.4 |
| Overall | ||
| CADD | 0.404 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.099%
Middle Eastern · 6/6,062 alleles
Filtering AF
0.043%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0294%
Overall
0.00347%
56/1,614,136 alleles · ultra-rare
exomes 38/1,461,812 · genomes 18/152,324 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.099% | 1,010 |
| African / African-American | 0.0453% | 2,207 |
| Admixed American | 0.00333% | 30,012 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,251 |
| South Asian | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000932% | 107,272 |
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.Pro1538=
- Coding
- c.4614C>T
- MANE Select
- NM_001376571
- Type
- single nucleotide variant
- Location
- chr11:47324336 (GRCh38)
- Gene constraint
- LOEUF 0.725 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 64.59
- Residue 1538
- a UniProt-annotated variant site (in deeah; uncertain significance); a UniProt-annotated variant site (in deeah and neddish; uncertain significance); a UniProt-annotated variant site (in neddish; impaired tnfa-induced activation of the map kinases erk1/2; enhanced susceptibility to tnfa-induced apoptosis; decreased egf internalization); a UniProt-annotated variant site (in neddish; 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-pro1538 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown