Is HBB p.Pro59Arg (c.176C>G) pathogenic?

HBB p.Pro59Arg (c.176C>G) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-05). AlphaMissense: likely benign (0.2112); Ultra-rare (popmax 0.0165%, mid); Associated with hemoglobinopathy.

What condition is associated with HBB p.Pro59Arg (c.176C>G)?

HBB p.Pro59Arg (c.176C>G) is associated with hemoglobinopathy (ClinVar).

How common is HBB p.Pro59Arg (c.176C>G) in the general population?

HBB p.Pro59Arg (c.176C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HBB p.Pro59Arg (c.176C>G)?

AlphaMissense predicts likely benign (score 0.2112) — an in-silico prediction, not a clinical call.

HBB p.Pro59Arg

c.176C>G · rs33991472 · VCV15398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemoglobinopathy

Computational evidence

Protein change
AlphaMissense	0.2112	likely benign
REVEL	0.703	pathogenic-leaning
SaProt	LLR -14.28	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 1	GERP 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	21.0	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

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,138 alleles · ultra-rare exomes 1/1,461,878 · genomes 0/152,260 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HBB
Protein: p.Pro59Arg
Coding: c.176C>G
MANE Select: NM_000518
dbSNP: rs33991472
Type: single nucleotide variant
Location: chr11:5226716 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 59: a UniProt-annotated variant site (in dhofar/yukuhashi); 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.Pro59fs Likely pathogenic ★★ 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
HBB c.93-2A>C Pathogenic ★★ same condition
HBB c.-138C>A Pathogenic/Likely pathogenic ★★ same condition
HBB c.-29G>A 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-pro59arg (accessed [today's date]).

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