Is HBB p.Val2Met (c.4G>A) pathogenic?

HBB p.Val2Met (c.4G>A) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.8857); Very rare (popmax 0.000774%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Val2Met (c.4G>A)?

HBB p.Val2Met (c.4G>A) is associated with beta thalassemia (ClinVar).

How common is HBB p.Val2Met (c.4G>A) in the general population?

HBB p.Val2Met (c.4G>A) is very rare (popmax 0.000774%, nfe) (gnomAD).

What do computational predictors say about HBB p.Val2Met (c.4G>A)?

AlphaMissense predicts likely pathogenic (score 0.8857) — an in-silico prediction, not a clinical call.

HBB p.Val2Met

c.4G>A · rs33958358 · VCV15359

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000774%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.8857	likely pathogenic
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -10.11	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 2.9	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	22.6	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 0.000774% European (non-Finnish) · 9/1,162,802 alleles

Filtering AF 0.000364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000264%

Overall 0.000564% 9/1,595,386 alleles · very rare exomes 9/1,443,092 · genomes 0/152,294 · joint denominator

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.Val2Met
Coding: c.4G>A
MANE Select: NM_000518
dbSNP: rs33958358
Type: single nucleotide variant
Location: chr11:5227018 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 2: a modified residue (n-acetylvaline); a modified residue (n-pyruvate 2-iminyl-valine; in hb a1b); a binding site; a UniProt-annotated variant site (in raleigh; o(2) affinity down)

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.Val2Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Val2fs Pathogenic same residue
HBB p.Val2Leu Uncertain significance ★ ⚠ same residue
HBB p.Val2= 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-val2met (accessed [today's date]).

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