Is HBB p.His98= (c.294C>T) pathogenic?

HBB p.His98= (c.294C>T) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0164%, mid); Associated with Fetal hemoglobin quantitative trait locus 1.

What condition is associated with HBB p.His98= (c.294C>T)?

HBB p.His98= (c.294C>T) is associated with Fetal hemoglobin quantitative trait locus 1, sickle cell disease, beta thalassemia (ClinVar).

How common is HBB p.His98= (c.294C>T) in the general population?

HBB p.His98= (c.294C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

HBB p.His98=

c.294C>T · rs34515413 · VCV439783

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Fetal hemoglobin quantitative trait locus 1

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 -9	GERP -2.9
Overall
CADD	3.503	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.0209% 337/1,613,958 alleles · ultra-rare exomes 303/1,461,828 · genomes 34/152,130 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.719%	139
Remaining individualsnot grpmax-eligible	0.0608%	1,644
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00834%	11,997
European (non-Finnish)	0.00653%	15,324
African / African-American	0.00401%	24,967

Ashkenazi Jewish 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.His98=
Coding: c.294C>T
MANE Select: NM_000518
dbSNP: rs34515413
Type: single nucleotide variant
Location: chr11:5226598 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 98: a UniProt-annotated variant site (in wood; o(2) affinity up); a UniProt-annotated variant site (in nagoya; o(2) affinity up; unstable); a UniProt-annotated variant site (in malmoe; o(2) affinity up); a UniProt-annotated variant site (in moriguchi); the globin domain

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

Disease context

Fetal hemoglobin quantitative trait locus 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sickle cell disease beta thalassemia

Similar variants

HBB p.His98Asn Likely pathogenic ★ ⚠ same residue
HBB p.His98Gln Pathogenic ★ same residue
HBB p.His98Leu Likely pathogenic ★ 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

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-his98 (accessed [today's date]).

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