Is HBB p.His3= (c.9T>C) pathogenic?

HBB p.His3= (c.9T>C) is classified Benign in HBB (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). Common (popmax 87.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with METHEMOGLOBINEMIA, BETA TYPE.

What condition is associated with HBB p.His3= (c.9T>C)?

HBB p.His3= (c.9T>C) is associated with METHEMOGLOBINEMIA, BETA TYPE, Heinz body anemia, dominant beta-thalassemia (ClinVar).

HBB p.His3=

Q: How common is HBB p.His3= (c.9T>C) in the general population?

HBB p.His3= (c.9T>C) is common (popmax 87.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.9T>C · rs713040 · VCV193106

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 87.2%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

METHEMOGLOBINEMIA, BETA TYPE

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -3.7
Overall
CADD	0.472	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 87.2% Middle Eastern · 5,270/6,044 alleles

Filtering AF 86.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 86.3%

Overall 81.6% 1,309,583/1,605,108 alleles · common exomes 1,185,386/1,452,948 · genomes 124,197/152,160 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	97.1%	1
Middle Easterngrpmax	87.2%	1
African / African-American	87.1%	1
Ashkenazi Jewishnot grpmax-eligible	86.3%	1
European (non-Finnish)	84.5%	1
Remaining individualsnot grpmax-eligible	80.9%	1
Finnishnot grpmax-eligible	79%	1
Admixed American	68.3%	1
South Asian	64.7%	2
East Asian	49.8%	2

Amish 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.His3=
Coding: c.9T>C
MANE Select: NM_000518
dbSNP: rs713040
Type: single nucleotide variant
Location: chr11:5227013 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 3: an α-helix; the globin domain; a UniProt-annotated variant site (in graz); a UniProt-annotated variant site (in okayama; o(2) affinity up); a UniProt-annotated variant site (in deer lodge; o(2) affinity up); a UniProt-annotated variant site (in fukuoka); a binding site

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

Disease context

METHEMOGLOBINEMIA, BETA TYPE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease alpha thalassemia spectrum beta-thalassemia HBB/LCRB beta thalassemia hereditary persistence of fetal hemoglobin malaria, susceptibility to erythrocytosis, familial, 6

Similar variants

HBB p.His3fs Pathogenic/Likely pathogenic ★★ same residue
HBB p.His3_Pro6delinsProGluValLysSerAlaTer Pathogenic same residue
HBB p.His3Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.His3Pro Uncertain significance ★ ⚠ same residue
HBB p.His3Gln Likely benign ★ 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

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-his3 (accessed [today's date]).

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