Is HBB p.Leu92= (c.276G>A) pathogenic?

HBB p.Leu92= (c.276G>A) is classified Likely benign in HBB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-09). Very rare (popmax 0.000169%, nfe).

How common is HBB p.Leu92= (c.276G>A) in the general population?

HBB p.Leu92= (c.276G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

HBB p.Leu92=

c.276G>A · rs1589892429 · VCV2010262

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 0.099	GERP 1.9, phastCons 0.93
Overall
CADD	6.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,114 alleles · very rare exomes 2/1,461,872 · genomes 0/152,242 · 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.Leu92=
Coding: c.276G>A
MANE Select: NM_000518
dbSNP: rs1589892429
Type: single nucleotide variant
Location: chr11:5226616 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 92: a UniProt-annotated variant site (in sabine; unstable); a UniProt-annotated variant site (in caribbean; o(2) affinity down; unstable); an α-helix; the globin domain

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

Similar variants

HBB p.Leu92Arg Uncertain significance ★★ ⚠ same residue
HBB p.Leu92Pro Pathogenic ★ same residue
HBB p.Leu92fs Likely pathogenic ★ same residue
HBB c.316-146T>G Pathogenic ★★★ same type
HBB c.316-197C>T Pathogenic ★★★ same type
HBB c.92+5G>C Pathogenic ★★★ same type
HBB c.-78A>C Pathogenic ★★★ same type
HBB c.*111A>G Pathogenic ★★★ same type

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-leu92 (accessed [today's date]).

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