Is HBB p.Leu69Phe (c.205C>T) pathogenic?

HBB p.Leu69Phe (c.205C>T) is classified Pathogenic/Likely pathogenic in HBB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-31). AlphaMissense: likely pathogenic (0.7112); Absent from gnomAD v4.1; Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Leu69Phe (c.205C>T)?

HBB p.Leu69Phe (c.205C>T) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Leu69Phe (c.205C>T) in the general population?

HBB p.Leu69Phe (c.205C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Leu69Phe (c.205C>T)?

AlphaMissense predicts likely pathogenic (score 0.7112) — an in-silico prediction, not a clinical call.

HBB p.Leu69Phe

c.205C>T · rs33961459 · VCV15613

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7112 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-thalassemia HBB/LCRB

Computational evidence

Protein change
AlphaMissense	0.7112	likely pathogenic ✓ concordant with ClinVar
REVEL	0.742	pathogenic-leaning
SaProt	LLR -8.95	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 -0.17	GERP -2.1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	17.95	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.Leu69Phe
Coding: c.205C>T
MANE Select: NM_000518
dbSNP: rs33961459
Type: single nucleotide variant
Location: chr11:5226687 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 69: a UniProt-annotated variant site (in brisbane; o(2) affinity up); a UniProt-annotated variant site (in mizuho; unstable); an α-helix; the globin domain

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 alpha thalassemia spectrum hereditary persistence of fetal hemoglobin malaria, susceptibility to erythrocytosis, familial, 6

Similar variants

HBB p.Leu69= 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
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-leu69phe (accessed [today's date]).

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