Is HBB p.Val2Ala (c.5T>C) pathogenic?

HBB p.Val2Ala (c.5T>C) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-22). AlphaMissense: likely pathogenic (0.6725); Very rare (popmax 0.000258%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Val2Ala (c.5T>C)?

HBB p.Val2Ala (c.5T>C) is associated with beta thalassemia (ClinVar).

How common is HBB p.Val2Ala (c.5T>C) in the general population?

HBB p.Val2Ala (c.5T>C) is very rare (popmax 0.000258%, nfe) (gnomAD).

What do computational predictors say about HBB p.Val2Ala (c.5T>C)?

AlphaMissense predicts likely pathogenic (score 0.6725) — an in-silico prediction, not a clinical call.

HBB p.Val2Ala

c.5T>C · rs33949930 · VCV15323

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000258%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.6725	likely pathogenic
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.65, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	20.2	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

Grpmax group 0.000258% European (non-Finnish) · 3/1,164,302 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,596,872 alleles · very rare exomes 3/1,444,680 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,860
European (non-Finnish)grpmax	0.000258%	388,101

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val2Ala
Coding: c.5T>C
MANE Select: NM_000518
dbSNP: rs33949930
Type: single nucleotide variant
Location: chr11:5227017 (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.Val2Met 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-val2ala (accessed [today's date]).

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