Is HBB p.Asp100Glu (c.300T>A) pathogenic?

HBB p.Asp100Glu (c.300T>A) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-22). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 8.47e-05%, nfe); Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Asp100Glu (c.300T>A)?

HBB p.Asp100Glu (c.300T>A) is associated with erythrocytosis, familial, 6 (ClinVar).

How common is HBB p.Asp100Glu (c.300T>A) in the general population?

HBB p.Asp100Glu (c.300T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HBB p.Asp100Glu (c.300T>A)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

HBB p.Asp100Glu

c.300T>A · rs34013622 · VCV917854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

erythrocytosis, familial, 6

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic · top 4% in HBB
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -11.86	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 2	GERP -3.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	19.75	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.2e-05% 1/1,614,068 alleles · very rare exomes 1/1,461,854 · genomes 0/152,214 · 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.Asp100Glu
Coding: c.300T>A
MANE Select: NM_000518
dbSNP: rs34013622
Type: single nucleotide variant
Location: chr11:5226592 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 100: a UniProt-annotated variant site (in coimbra; o(2) affinity up); the globin domain

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

Disease context

erythrocytosis, familial, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HBB p.Asp100Tyr Pathogenic ★ same residue
HBB p.Asp100= Likely benign ★ same residue
HBB c.316-197C>T Pathogenic ★★★ same condition
HBB c.92+5G>C Pathogenic ★★★ same condition
HBB c.-78A>C Pathogenic ★★★ same condition
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same condition
HBB p.Lys18Ter Pathogenic ★★★ same condition
HBB c.-75G>C Uncertain significance ★★★ 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-asp100glu (accessed [today's date]).

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