Is HBB p.Ala130Val (c.389C>T) pathogenic?

HBB p.Ala130Val (c.389C>T) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-29). AlphaMissense: ambiguous (0.3754); Ultra-rare (popmax 0.0213%, afr); Associated with beta thalassemia.

What condition is associated with HBB p.Ala130Val (c.389C>T)?

HBB p.Ala130Val (c.389C>T) is associated with beta thalassemia, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Ala130Val (c.389C>T) in the general population?

HBB p.Ala130Val (c.389C>T) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about HBB p.Ala130Val (c.389C>T)?

AlphaMissense predicts ambiguous (score 0.3754) — an in-silico prediction, not a clinical call.

HBB p.Ala130Val

c.389C>T · rs111645889 · VCV15245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.3754	ambiguous
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.0213% African / African-American · 16/75,022 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00124% 20/1,613,962 alleles · ultra-rare exomes 9/1,461,702 · genomes 11/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,689
Remaining individualsnot grpmax-eligible	0.0032%	31,252
Admixed American	0.00167%	60,020
South Asian	0.0011%	91,076

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.Ala130Val
Coding: c.389C>T
MANE Select: NM_000518
dbSNP: rs111645889
Type: single nucleotide variant
Location: chr11:5225653 (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

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

Similar variants

HBB p.Ala130Pro 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-ala130val (accessed [today's date]).

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