Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 11 submitters
gnomAD v4.1
Common
common (popmax 73.3%, afr) — too common for a highly-penetrant pathogenic allele
Conditions
2
IRIDA syndrome
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 -7.5 | GERP -3.4 |
| Overall | ||
| CADD | 0.02 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
73.3%
African / African-American · 54,928/74,906 alleles
Filtering AF
72.8%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 72.6%
Overall
53.9%
869,164/1,611,200 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 73.3% | 1 |
| Amishnot grpmax-eligible | 60.4% | 2 |
| Finnishnot grpmax-eligible | 57.2% | 2 |
| Middle Eastern | 55.5% | 2 |
| Remaining individualsnot grpmax-eligible | 53.7% | 2 |
| European (non-Finnish) | 53.7% | 2 |
| Ashkenazi Jewishnot grpmax-eligible | 53.6% | 2 |
| Admixed American | 49.9% | 2 |
| East Asian | 46% | 2 |
| South Asian | 45.3% | 2 |
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
- TMPRSS6
- Protein
- p.Asp512=
- Coding
- c.1536C>T
- MANE Select
- NM_001374504
- dbSNP
- rs4820268
- Type
- single nucleotide variant
- Location
- chr22:37073551 (GRCh38)
- Gene constraint
- LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 84.69 · 1 PDB
- Residue 512
- a β-strand; a disulfide bond; the ldl-receptor class a 2 domain
Disease context
IRIDA syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: microcytic anemia
For IRIDA syndrome (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Infancy, Neonatal
Similar variants
- TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same residue
- TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
- TMPRSS6 p.Ser552Ter Pathogenic ★★ same condition
- TMPRSS6 p.Tyr346Ter Likely pathogenic ★★ same condition
- TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
- TMPRSS6 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
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/tmprss6-p-asp512 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown