Is HBB p.Met1Ile (c.3G>A) pathogenic?

HBB p.Met1Ile (c.3G>A) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-07). Absent from gnomAD v4.1; Associated with dominant beta-thalassemia.

What condition is associated with HBB p.Met1Ile (c.3G>A)?

HBB p.Met1Ile (c.3G>A) is associated with dominant beta-thalassemia, beta thalassemia (ClinVar).

How common is HBB p.Met1Ile (c.3G>A) in the general population?

HBB p.Met1Ile (c.3G>A) is absent from gnomAD v4.1 (gnomAD).

How is Unstable beta globin chain variant disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

HBB p.Met1Ile

c.3G>A · rs33930702 · VCV15519

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

dominant beta-thalassemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.775	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

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.Met1Ile
Coding: c.3G>A
MANE Select: NM_000518
dbSNP: rs33930702
Type: single nucleotide variant
Location: chr11:5227019 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB

Full HBB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dominant beta-thalassemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: beta thalassemia

For Unstable beta globin chain variant disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

HBB p.Met1Arg Pathogenic ★★ same residue
HBB p.Met1Leu Pathogenic/Likely pathogenic ★★ same residue
HBB p.Met1Lys Pathogenic/Likely pathogenic ★★ same residue
HBB p.Met1Thr Pathogenic ★★ same residue
HBB p.Met1Val Pathogenic ★★ 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

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-met1ile (accessed [today's date]).

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