Is HBB p.Lys18Ter (c.52A>T) pathogenic?

HBB p.Lys18Ter (c.52A>T) is classified Pathogenic in HBB (ClinVar, Expert panel, 21 submitters; last evaluated 2026-04-30). Ultra-rare (popmax 0.0401%, eas); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Lys18Ter (c.52A>T)?

HBB p.Lys18Ter (c.52A>T) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Lys18Ter (c.52A>T) in the general population?

HBB p.Lys18Ter (c.52A>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

HBB p.Lys18Ter

c.52A>T · rs33986703 · VCV15401

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 21 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Conditions

beta-thalassemia HBB/LCRB

ClinGen expert panel — Hemoglobinopathy VCEP

Pathogenic for beta-thalassemia HBB/LCRB. Applied ACMG criteria (verbatim):

PVS1_Strong PM2_Supporting PM3_VeryStrong PP1_Moderate PS4

Curation rationale (ClinGen, verbatim)

The c.52A>T (p.Lys18*) variant in HBB is a nonsense variant predicted to cause loss of function of the protein [PVS1_S; PMID: 68654]. The variant has been reported to segregate with beta thalassemia intermedia in 3 affected family members from 3 families. The total number of unaffected segregations is 1, giving a total LOD score of 1.93 [PP1_M; PMID: 31579136; 26029792; 88735]. This variant has been detected in 5 individuals with beta thalassemia. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant, confirmed in trans by family testing, and 2 individuals were homozygous for the variant. Total PM3 points are 4.0 [PM3_VS; PMID: 88735; 31579136; 26029792; 31037981; 11168520]. This variant has been reported in 3 unrelated individuals displaying a hematological phenotype consistent with beta-thalassemia trait with reduced MCV (<79 fl) and MCH (<27 pg) and increased HbA2 (>3.5%), giving a total score of 4.5 [PS4; PMID: 31579136; 11168520; 26029792]. The minor allele frequency in gnomAD v4.1 is 0.00001177 (19/1614014 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]. In summary, this variant meets the criteria to be classified as pathogenic for beta-thalassemia HBB/LCRB (MONDO:0013517) in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VECP (specification version 1.0.0): PVS1_S, PM3_VS, PP1_M, PS4, PM2_P

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.41	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.8	GERP 1.9, phastCons 0.99
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% East Asian · 18/44,876 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00118% 19/1,614,014 alleles · ultra-rare exomes 10/1,461,684 · genomes 9/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Lys18Ter
Coding: c.52A>T
MANE Select: NM_000518
dbSNP: rs33986703
Type: single nucleotide variant
Location: chr11:5226970 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 18: the globin domain; a UniProt-annotated variant site (in nagasaki); a UniProt-annotated variant site (in j-amiens); a UniProt-annotated variant site (in nikosia)

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

Disease context

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

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease alpha thalassemia spectrum beta thalassemia hereditary persistence of fetal hemoglobin malaria, susceptibility to erythrocytosis, familial, 6

Similar variants

HBB p.Lys18fs Pathogenic ★★ same residue
HBB p.Lys18_Val19insTer Likely pathogenic ★ same residue
HBB p.Lys18= Likely benign ★ 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-lys18ter (accessed [today's date]).

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