TMPRSS6 p.Phe686Leu
c.2058C>G · rs375189210 · VCV341581
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3769 | ambiguous |
|---|---|---|
| REVEL | 0.256 | benign-leaning |
| SaProt | LLR -6.16 | tolerated |
| ⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4.9 | GERP -0.21, phastCons 1 |
| Regional constraint | o/e 0.95 | unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic |
| Overall | ||
| CADD | 17.61 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F695L vs ClinVar F686L) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.725% | 138 |
| Remaining individualsnot grpmax-eligible | 0.0478% | 2,094 |
| Admixed Americangrpmax | 0.00556% | 17,986 |
| European (non-Finnish) | 0.00371% | 26,939 |
| African / African-American | 0.00136% | 73,758 |
| South Asian | 0.00116% | 86,170 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Phe686Leu
- Coding
- c.2058C>G
- MANE Select
- NM_001374504
- dbSNP
- rs375189210
- Type
- single nucleotide variant
- Location
- chr22:37069128 (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 686
- the peptidase s1 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 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS6 p.Asp512Asn 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-phe686leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown