Is HBB p.Trp38fs (c.112del) pathogenic?

HBB p.Trp38fs (c.112del) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-08-14). Ultra-rare (popmax 0.0165%, mid); Associated with malaria, susceptibility to.

What condition is associated with HBB p.Trp38fs (c.112del)?

HBB p.Trp38fs (c.112del) is associated with malaria, susceptibility to, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Trp38fs (c.112del) in the general population?

HBB p.Trp38fs (c.112del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

HBB p.Trp38fs

c.112del · rs63750532 · VCV15431

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

malaria, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000186% 3/1,614,122 alleles · ultra-rare exomes 3/1,461,862 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Trp38fs
Coding: c.112del
MANE Select: NM_000518
dbSNP: rs63750532
Type: Deletion
Location: chr11:5226780 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 38: a UniProt-annotated variant site (in howick); a UniProt-annotated variant site (in rothschild; o(2) affinity down); a UniProt-annotated variant site (in hirose; o(2) affinity up); 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

malaria, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

HBB p.Trp38Ter Pathogenic ★★★ same residue
HBB c.315+2del Pathogenic/Likely pathogenic ★★ same condition
HBB c.93-22_95del Pathogenic ★★ same condition
HBB c.*110_*111del Pathogenic/Likely pathogenic ★★ same condition
HBB c.*110_*114del Pathogenic/Likely pathogenic ★★ same condition
HBB p.Glu23fs Pathogenic/Likely pathogenic ★★ same condition
HBB p.Glu7fs Pathogenic ★★ same condition
HBB p.Gly70fs Pathogenic/Likely 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-trp38fs (accessed [today's date]).

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