Is HBB p.Ala54= (c.162T>C) pathogenic?

HBB p.Ala54= (c.162T>C) is classified Uncertain significance in HBB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-19). Very rare (popmax 8.47e-05%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Ala54= (c.162T>C)?

HBB p.Ala54= (c.162T>C) is associated with beta thalassemia (ClinVar).

How common is HBB p.Ala54= (c.162T>C) in the general population?

HBB p.Ala54= (c.162T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

HBB p.Ala54=

c.162T>C · VCV4069104

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

beta thalassemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.8	GERP -1.2
Overall
CADD	7.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,878 · genomes 0/152,314 · 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.Ala54=
Coding: c.162T>C
MANE Select: NM_000518
Type: single nucleotide variant
Location: chr11:5226730 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 54: 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.Ala54Thr Likely pathogenic ★ ⚠ same residue
HBB p.Ala54Val 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
HBB p.Ala28Ser 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-ala54 (accessed [today's date]).

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