Is HBB p.Ala130Pro (c.388G>C) pathogenic?

HBB p.Ala130Pro (c.388G>C) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.9586); Absent from gnomAD v4.1; Associated with beta thalassemia.

What condition is associated with HBB p.Ala130Pro (c.388G>C)?

HBB p.Ala130Pro (c.388G>C) is associated with beta thalassemia (ClinVar).

How common is HBB p.Ala130Pro (c.388G>C) in the general population?

HBB p.Ala130Pro (c.388G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Ala130Pro (c.388G>C)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

HBB p.Ala130Pro

c.388G>C · rs35939430 · VCV15146

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9586 · 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	0.9586	likely pathogenic
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -15.18	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 -0.14	GERP 0.1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	21.2	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.Ala130Pro
Coding: c.388G>C
MANE Select: NM_000518
dbSNP: rs35939430
Type: single nucleotide variant
Location: chr11:5225654 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 130: a UniProt-annotated variant site (in crete; o(2) affinity up; unstable); a UniProt-annotated variant site (in la desirade; o(2) affinity down; unstable); 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.Ala130Val Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Ala130Thr Uncertain significance ★ ⚠ 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-ala130pro (accessed [today's date]).

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