Is HBB p.Pro101Thr (c.301C>A) pathogenic?

HBB p.Pro101Thr (c.301C>A) is classified Uncertain significance in HBB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-12). AlphaMissense: likely pathogenic (0.9461); Absent from gnomAD v4.1; Associated with beta thalassemia.

What condition is associated with HBB p.Pro101Thr (c.301C>A)?

HBB p.Pro101Thr (c.301C>A) is associated with beta thalassemia (ClinVar).

How common is HBB p.Pro101Thr (c.301C>A) in the general population?

HBB p.Pro101Thr (c.301C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Pro101Thr (c.301C>A)?

AlphaMissense predicts likely pathogenic (score 0.9461) — an in-silico prediction, not a clinical call.

HBB p.Pro101Thr

c.301C>A · VCV4069105

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9461 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.9461	likely pathogenic
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Pro101Thr
Coding: c.301C>A
MANE Select: NM_000518
Type: single nucleotide variant
Location: chr11:5226591 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 101: a UniProt-annotated variant site (in brigham; o(2) affinity up); a UniProt-annotated variant site (in new mexico); 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.Pro101Arg Uncertain significance ★ ⚠ same residue
HBB p.Pro101= 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
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-pro101thr (accessed [today's date]).

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