HBA2 p.Ala22Pro
c.64G>C · rs281864817 · VCV801178
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0157%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.572 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -0.68 | |
| Regional constraint | o/e 1.06 | unconstrained · MANE · 239 bp · p 0.81 · regional, not allelic |
| Overall | ||
| CADD | 16.93 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0157%
South Asian · 7/44,694 alleles
Filtering AF
0.00728%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00516%
Overall
0.00216%
9/416,564 alleles · ultra-rare
exomes 9/411,840 · genomes 0/4,724 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0157% | 6,385 |
| Remaining individualsnot grpmax-eligible | 0.00423% | 23,638 |
| European (non-Finnish) | 0.000402% | 248,902 |
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
- HBA2
- Protein
- p.Ala22Pro
- Coding
- c.64G>C
- MANE Select
- NM_000517
- dbSNP
- rs281864817
- Type
- single nucleotide variant
- Location
- chr16:172976 (GRCh38)
- Gene constraint
- LOEUF 1.915 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 98.04 · 348 PDB
- Residue 22
- an α-helix; the globin domain; a UniProt-annotated variant site (in j-nyanza); a UniProt-annotated variant site (in fontainebleau)
Similar variants
- HBA2 p.Ala22fs Likely pathogenic ★ same residue
- HBA2 p.Cys105Arg Likely pathogenic ★★★ same type
- HBA2 p.Leu126Arg Likely pathogenic ★★★ same type
- HBA2 c.*98T>C Uncertain significance ★★★ same type
- HBA2 c.95+27C>T Benign ★★★ same type
- HBA2 c.-24C>G Benign ★★★ same type
- HBA2 c.*107A>G Benign ★★★ same type
- HBA2 c.300+1G>A Likely 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/hba2-p-ala22pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown