Is HBB p.Arg31Ser (c.93G>T) pathogenic?

HBB p.Arg31Ser (c.93G>T) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-19). AlphaMissense: likely pathogenic (0.9539); Very rare (popmax 0.000339%, nfe); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Arg31Ser (c.93G>T)?

HBB p.Arg31Ser (c.93G>T) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, beta thalassemia (ClinVar).

How common is HBB p.Arg31Ser (c.93G>T) in the general population?

HBB p.Arg31Ser (c.93G>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about HBB p.Arg31Ser (c.93G>T)?

AlphaMissense predicts likely pathogenic (score 0.9539) — an in-silico prediction, not a clinical call.

HBB p.Arg31Ser

c.93G>T · rs1135071 · VCV15368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-thalassemia HBB/LCRB

Computational evidence

Protein change
AlphaMissense	0.9539	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -13.51	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 1.5	GERP 0.98, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,780 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.0138% 222/1,613,862 alleles · very rare exomes 184/1,461,592 · genomes 38/152,270 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.33%	303
Remaining individualsnot grpmax-eligible	0.0112%	8,928
European (non-Finnish)grpmax	0.000339%	294,945

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg31Ser
Coding: c.93G>T
MANE Select: NM_000518
dbSNP: rs1135071
Type: single nucleotide variant
Location: chr11:5226799 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 31: a UniProt-annotated variant site (in tacoma; 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

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

Also linked: Heinz body anemia beta thalassemia

Similar variants

HBB p.Arg31= Likely pathogenic ★★ same residue
HBB p.Arg31Gly Pathogenic/Likely pathogenic ★★ same residue
HBB p.Arg31Thr Pathogenic ★★ same residue
HBB p.Arg31dup Pathogenic same residue
HBB p.Arg31fs Pathogenic same residue
HBB p.Arg31Met Likely pathogenic ★ same residue
HBB c.316-146T>G Pathogenic ★★★ same condition
HBB c.316-197C>T 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-arg31ser (accessed [today's date]).

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