Is HBB p.Val12Ile (c.34G>A) pathogenic?

HBB p.Val12Ile (c.34G>A) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-22). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.00801%, afr); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Val12Ile (c.34G>A)?

HBB p.Val12Ile (c.34G>A) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Val12Ile (c.34G>A) in the general population?

HBB p.Val12Ile (c.34G>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about HBB p.Val12Ile (c.34G>A)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

HBB p.Val12Ile

c.34G>A · rs33974228 · VCV15189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

beta-thalassemia HBB/LCRB

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -1.9
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	4.389	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,894 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00546% 88/1,613,042 alleles · very rare exomes 79/1,460,830 · genomes 9/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,482
Admixed American	0.00667%	15,001
European (non-Finnish)	0.00628%	15,934
Remaining individualsnot grpmax-eligible	0.0032%	31,230
Finnishnot grpmax-eligible	0.00156%	64,046
South Asian	0.0011%	91,068

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.Val12Ile
Coding: c.34G>A
MANE Select: NM_000518
dbSNP: rs33974228
Type: single nucleotide variant
Location: chr11:5226988 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 12: an α-helix; the globin domain; a UniProt-annotated variant site (in windsor; o(2) affinity up; unstable); a UniProt-annotated variant site (in hamilton)

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

Disease context

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

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

Similar variants

HBB p.Val12Phe 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
HBB p.Lys18Ter 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-val12ile (accessed [today's date]).

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