HMBS p.Arg22=
c.66C>T · rs531691068 · VCV1528776
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.075%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>G here scores Δ0.66 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -5.1 | GERP -4.7 |
| Overall | ||
| CADD | 3.993 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.075%
Admixed American · 45/60,016 alleles
Filtering AF
0.0575%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0513%
Overall
0.00452%
73/1,614,052 alleles · ultra-rare
exomes 65/1,461,816 · genomes 8/152,236 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.075% | 1,334 |
| Finnishnot grpmax-eligible | 0.00312% | 32,005 |
| East Asian | 0.00223% | 44,890 |
| European (non-Finnish) | 0.00203% | 49,166 |
| African / African-American | 0.00133% | 75,018 |
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
- HMBS
- Protein
- p.Arg22=
- Coding
- c.66C>T
- MANE Select
- NM_000190
- dbSNP
- rs531691068
- Type
- single nucleotide variant
- Location
- chr11:119088287 (GRCh38)
- Gene constraint
- LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 90.54 · 11 PDB
- Residue 22
- a UniProt-annotated variant site (in aip); a β-strand
Similar variants
- HMBS p.Arg22His Uncertain significance ★★ ⚠ same residue
- HMBS p.Arg22Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
- HMBS c.160+5G>C Pathogenic/Likely pathogenic ★★ same type
- HMBS c.345-1G>A Pathogenic ★★ same type
- HMBS c.613-1G>A Pathogenic ★★ same type
- HMBS c.826-2A>T Pathogenic/Likely pathogenic ★★ same type
- HMBS c.912+2T>C Pathogenic ★★ same type
- HMBS c.913-1G>A 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/hmbs-p-arg22 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown