Is HBB p.Val2Leu (c.4G>T) pathogenic?

HBB p.Val2Leu (c.4G>T) is classified Uncertain significance in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-24). AlphaMissense: likely pathogenic (0.7778); No allele count reported in gnomAD v4.1 (AN 1,595,386); Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Val2Leu (c.4G>T)?

HBB p.Val2Leu (c.4G>T) is associated with erythrocytosis, familial, 6, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Val2Leu (c.4G>T) in the general population?

HBB p.Val2Leu (c.4G>T) is no allele count reported in gnomAD v4.1 (AN 1,595,386) (gnomAD).

What do computational predictors say about HBB p.Val2Leu (c.4G>T)?

AlphaMissense predicts likely pathogenic (score 0.7778) — an in-silico prediction, not a clinical call.

HBB p.Val2Leu

c.4G>T · rs33958358 · VCV15558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7778 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,595,386)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

erythrocytosis, familial, 6

Computational evidence

Protein change
AlphaMissense	0.7778	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -9.06	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 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	22.2	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

No allele count reported in gnomAD v4.1 (AN 1,595,386). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HBB
Protein: p.Val2Leu
Coding: c.4G>T
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

erythrocytosis, familial, 6 — 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

Similar variants

HBB p.Val2Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Val2Met Conflicting classifications of pathogenicity ★ ⚠ 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
HBB c.*111A>G 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-val2leu (accessed [today's date]).

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