Is HBB p.Leu29Pro (c.86T>C) pathogenic?

HBB p.Leu29Pro (c.86T>C) is classified Pathogenic in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.9786); Absent from gnomAD v4.1; Associated with hemoglobinopathy.

What condition is associated with HBB p.Leu29Pro (c.86T>C)?

HBB p.Leu29Pro (c.86T>C) is associated with hemoglobinopathy (ClinVar).

How common is HBB p.Leu29Pro (c.86T>C) in the general population?

HBB p.Leu29Pro (c.86T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Leu29Pro (c.86T>C)?

AlphaMissense predicts likely pathogenic (score 0.9786) — an in-silico prediction, not a clinical call.

HBB p.Leu29Pro

c.86T>C · rs33916412 · VCV15183

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9786 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemoglobinopathy

Computational evidence

Protein change
AlphaMissense	0.9786	likely pathogenic ✓ concordant with ClinVar
REVEL	0.989	strongly pathogenic-leaning
SaProt	LLR -15.11	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 9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	26.7	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

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.Leu29Pro
Coding: c.86T>C
MANE Select: NM_000518
dbSNP: rs33916412
Type: single nucleotide variant
Location: chr11:5226936 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 29: a UniProt-annotated variant site (in genova/hyogo; unstable); a UniProt-annotated variant site (in st louis); an α-helix; the globin domain

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

Disease context

hemoglobinopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HBB p.Leu29fs Pathogenic ★★ same residue
HBB p.Leu29Arg Likely pathogenic ★ same residue
HBB p.Leu29Val Uncertain significance ★ ⚠ same residue
HBB p.Leu29= Likely benign ★ same residue
HBB c.*111A>G Pathogenic ★★★ same condition
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same condition
HBB p.Trp38Ter Pathogenic ★★★ same condition
HBB p.Val127Gly Uncertain significance ★★★ ⚠ 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-leu29pro (accessed [today's date]).

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