Is HBB p.Phe46Cys (c.137T>G) pathogenic?

HBB p.Phe46Cys (c.137T>G) is classified Likely pathogenic in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-16). AlphaMissense: likely pathogenic (0.9701); Absent from gnomAD v4.1; Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Phe46Cys (c.137T>G)?

HBB p.Phe46Cys (c.137T>G) is associated with erythrocytosis, familial, 6, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Phe46Cys (c.137T>G) in the general population?

HBB p.Phe46Cys (c.137T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Phe46Cys (c.137T>G)?

AlphaMissense predicts likely pathogenic (score 0.9701) — an in-silico prediction, not a clinical call.

HBB p.Phe46Cys

c.137T>G · rs33978338 · VCV15546

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9701 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

erythrocytosis, familial, 6

Computational evidence

Protein change
AlphaMissense	0.9701	likely pathogenic ✓ concordant with ClinVar
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -13.95	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	25.7	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.Phe46Cys
Coding: c.137T>G
MANE Select: NM_000518
dbSNP: rs33978338
Type: single nucleotide variant
Location: chr11:5226755 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 46: a UniProt-annotated variant site (in cheverly; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain

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.Phe46fs Pathogenic ★★ same residue
HBB p.Phe46Ser 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
HBB c.-78A>C Pathogenic ★★★ same condition
HBB c.*111A>G Pathogenic ★★★ same condition
HBB p.Ala28Ser 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-phe46cys (accessed [today's date]).

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