Is HBB p.Asn20Ser (c.59A>G) pathogenic?

HBB p.Asn20Ser (c.59A>G) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0784); Absent from gnomAD v4.1; Associated with beta thalassemia.

What condition is associated with HBB p.Asn20Ser (c.59A>G)?

HBB p.Asn20Ser (c.59A>G) is associated with beta thalassemia (ClinVar).

How common is HBB p.Asn20Ser (c.59A>G) in the general population?

HBB p.Asn20Ser (c.59A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Asn20Ser (c.59A>G)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

HBB p.Asn20Ser

c.59A>G · rs33972047 · VCV15258

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign ⚠ discordant with ClinVar
REVEL	0.46	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.82	donor gain · deltas
Pangolin	Δ0.54	loss · gain 0.53 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 0.83	GERP 1.9
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	26.9	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.Asn20Ser
Coding: c.59A>G
MANE Select: NM_000518
dbSNP: rs33972047
Type: single nucleotide variant
Location: chr11:5226963 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 20: the globin domain; a UniProt-annotated variant site (in alamo); a UniProt-annotated variant site (in d-ouleh rabah); a UniProt-annotated variant site (in malay)

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

Disease context

beta thalassemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HBB p.Asn20= Conflicting classifications of pathogenicity ★ same residue
HBB p.Asn20Lys 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-asn20ser (accessed [today's date]).

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