Is HBB p.Ser45Cys (c.134C>G) pathogenic?

HBB p.Ser45Cys (c.134C>G) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-16). AlphaMissense: likely benign (0.2294); Absent from gnomAD v4.1.

How common is HBB p.Ser45Cys (c.134C>G) in the general population?

HBB p.Ser45Cys (c.134C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Ser45Cys (c.134C>G)?

AlphaMissense predicts likely benign (score 0.2294) — an in-silico prediction, not a clinical call.

HBB p.Ser45Cys

c.134C>G · rs34868397 · VCV15267

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2294 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2294	likely benign
REVEL	0.711	pathogenic-leaning
SaProt	LLR -11.12	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.4	GERP -3.7
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	14.12	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.Ser45Cys
Coding: c.134C>G
MANE Select: NM_000518
dbSNP: rs34868397
Type: single nucleotide variant
Location: chr11:5226758 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 45: a UniProt-annotated variant site (in mississippi); an α-helix; a modified residue (phosphoserine); the globin domain

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

Similar variants

HBB p.Ser45= Likely benign ★ same residue
HBB c.316-146T>G Pathogenic ★★★ same type
HBB c.316-197C>T Pathogenic ★★★ same type
HBB c.92+5G>C Pathogenic ★★★ same type
HBB c.-78A>C Pathogenic ★★★ same type
HBB c.*111A>G Pathogenic ★★★ same type
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same type
HBB p.Lys18Ter Pathogenic ★★★ same type

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-ser45cys (accessed [today's date]).

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