Is HBB p.Glu23Val (c.68A>T) pathogenic?

HBB p.Glu23Val (c.68A>T) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-07-09). AlphaMissense: likely benign (0.0826); Absent from gnomAD v4.1; Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Glu23Val (c.68A>T)?

HBB p.Glu23Val (c.68A>T) is associated with erythrocytosis, familial, 6, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Glu23Val (c.68A>T) in the general population?

HBB p.Glu23Val (c.68A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Glu23Val (c.68A>T)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

HBB p.Glu23Val

c.68A>T · rs33936254 · VCV15149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

erythrocytosis, familial, 6

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -0.86
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	17.5	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

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.Glu23Val
Coding: c.68A>T
MANE Select: NM_000518
dbSNP: rs33936254
Type: single nucleotide variant
Location: chr11:5226954 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 23: an α-helix; the globin domain; a UniProt-annotated variant site (in g-coushatta/g-saskatoon/g-taegu/hsin chu); a UniProt-annotated variant site (in g-taipei); a UniProt-annotated variant site (in e-saskatoon); a UniProt-annotated variant site (in d-iran); a UniProt-annotated variant site (in d-granada)

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 alpha thalassemia spectrum beta-thalassemia HBB/LCRB hereditary persistence of fetal hemoglobin malaria, susceptibility to

Similar variants

HBB p.Glu23Ter Pathogenic ★★ same residue
HBB p.Glu23Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Glu23Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Glu23Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Glu23Lys Conflicting classifications of pathogenicity ★ ⚠ 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-glu23val (accessed [today's date]).

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