Is HBB p.Ala129= (c.387T>A) pathogenic?

HBB p.Ala129= (c.387T>A) is classified Likely benign in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-09). Very rare (popmax 0.000424%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Ala129= (c.387T>A)?

HBB p.Ala129= (c.387T>A) is associated with beta thalassemia (ClinVar).

How common is HBB p.Ala129= (c.387T>A) in the general population?

HBB p.Ala129= (c.387T>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

HBB p.Ala129=

c.387T>A · rs1248780802 · VCV991115

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

beta thalassemia

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 2.4	GERP 0.64, phastCons 0.001
Overall
CADD	10.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,938 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,056 alleles · very rare exomes 5/1,461,794 · genomes 0/152,262 · joint denominator

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: HBB
Protein: p.Ala129=
Coding: c.387T>A
MANE Select: NM_000518
dbSNP: rs1248780802
Type: single nucleotide variant
Location: chr11:5225655 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 129: a UniProt-annotated variant site (in j-guantanamo; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain

Full HBB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

beta thalassemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HBB p.Ala129Thr Uncertain significance ★★ ⚠ same residue
HBB p.Ala129Asp Uncertain significance ★ ⚠ same residue
HBB p.Ala129Val Uncertain significance ★ ⚠ same residue
HBB c.316-146T>G Pathogenic ★★★ same condition
HBB c.316-197C>T Pathogenic ★★★ same condition
HBB c.92+5G>C Pathogenic ★★★ same condition
HBB c.-78A>C Pathogenic ★★★ same condition
HBB c.*111A>G Pathogenic ★★★ 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/hbb-p-ala129 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown