Is HBB p.Phe43Ser (c.128T>C) pathogenic?

HBB p.Phe43Ser (c.128T>C) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-03-25). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with Heinz body anemia.

What condition is associated with HBB p.Phe43Ser (c.128T>C)?

HBB p.Phe43Ser (c.128T>C) is associated with Heinz body anemia, beta thalassemia (ClinVar).

How common is HBB p.Phe43Ser (c.128T>C) in the general population?

HBB p.Phe43Ser (c.128T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Phe43Ser (c.128T>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

HBB p.Phe43Ser

c.128T>C · rs34378160 · VCV15190

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Heinz body anemia

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 3% in HBB
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -12.62	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	26.3	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.Phe43Ser
Coding: c.128T>C
MANE Select: NM_000518
dbSNP: rs34378160
Type: single nucleotide variant
Location: chr11:5226764 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 43: a UniProt-annotated variant site (in louisville; unstable); a UniProt-annotated variant site (in hammersmith); a UniProt-annotated variant site (in bruxelles); the globin domain

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

Disease context

Heinz body anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: beta thalassemia

Similar variants

HBB p.Phe43Leu Likely pathogenic ★ same residue
HBB p.Phe43Ile Likely pathogenic same residue
HBB p.Phe43del Conflicting classifications of pathogenicity ★ same residue
HBB p.Phe43Val Pathogenic 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

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-phe43ser (accessed [today's date]).

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