Is HBB p.Tyr36= (c.108C>T) pathogenic?

HBB p.Tyr36= (c.108C>T) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-05). Very rare (popmax 0.00669%, eas); Associated with dominant beta-thalassemia.

What condition is associated with HBB p.Tyr36= (c.108C>T)?

HBB p.Tyr36= (c.108C>T) is associated with dominant beta-thalassemia, Heinz body anemia, sickle cell disease (ClinVar).

How common is HBB p.Tyr36= (c.108C>T) in the general population?

HBB p.Tyr36= (c.108C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

How is Unstable beta globin chain variant disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

HBB p.Tyr36=

c.108C>T · rs33982568 · VCV1544548

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

dominant 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 1.6	GERP 1, phastCons 1
Overall
CADD	8.018	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,876 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000681% 11/1,614,142 alleles · very rare exomes 11/1,461,846 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,959
European (non-Finnish)	0.000678%	147,500

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.Tyr36=
Coding: c.108C>T
MANE Select: NM_000518
dbSNP: rs33982568
Type: single nucleotide variant
Location: chr11:5226784 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 36: a UniProt-annotated variant site (in philly; o(2) affinity up; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); the globin domain

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

Disease context

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

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

For Unstable beta globin chain variant disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

HBB p.Tyr36Ter Pathogenic ★★ same residue
HBB p.Tyr36fs Pathogenic same residue
HBB p.Tyr36Cys Likely pathogenic ★ 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-tyr36 (accessed [today's date]).

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