Is HBB p.Asp53His (c.157G>C) pathogenic?

HBB p.Asp53His (c.157G>C) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-12). AlphaMissense: likely benign (0.2016); Absent from gnomAD v4.1; Associated with beta thalassemia.

What condition is associated with HBB p.Asp53His (c.157G>C)?

HBB p.Asp53His (c.157G>C) is associated with beta thalassemia (ClinVar).

How common is HBB p.Asp53His (c.157G>C) in the general population?

HBB p.Asp53His (c.157G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Asp53His (c.157G>C)?

AlphaMissense predicts likely benign (score 0.2016) — an in-silico prediction, not a clinical call.

HBB p.Asp53His

c.157G>C · rs33961886 · VCV15362

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2016 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.2016	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -3.7
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	6.208	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HBB
Protein: p.Asp53His
Coding: c.157G>C
MANE Select: NM_000518
dbSNP: rs33961886
Type: single nucleotide variant
Location: chr11:5226735 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 53: a UniProt-annotated variant site (in ocho rios); a UniProt-annotated variant site (in summer hill); 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.Asp53Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Asp53fs Pathogenic same residue
HBB p.Asp53Ala Uncertain significance ★ ⚠ same residue
HBB p.Asp53= 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

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-asp53his (accessed [today's date]).

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