Is HBB p.Leu92Arg (c.275T>G) pathogenic?

HBB p.Leu92Arg (c.275T>G) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-10-05). AlphaMissense: ambiguous (0.5398); Very rare (popmax 0.00133%, afr).

How common is HBB p.Leu92Arg (c.275T>G) in the general population?

HBB p.Leu92Arg (c.275T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about HBB p.Leu92Arg (c.275T>G)?

AlphaMissense predicts ambiguous (score 0.5398) — an in-silico prediction, not a clinical call.

HBB p.Leu92Arg

c.275T>G · rs33917785 · VCV15131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5398	ambiguous
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	24.7	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 0.00133% African / African-American · 1/75,038 alleles

Overall 6.2e-05% 1/1,614,148 alleles · very rare exomes 1/1,461,878 · genomes 0/152,270 · 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.Leu92Arg
Coding: c.275T>G
MANE Select: NM_000518
dbSNP: rs33917785
Type: single nucleotide variant
Location: chr11:5226617 (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.Leu92= Likely benign ★★ 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-leu92arg (accessed [today's date]).

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