Is HBB p.His3Arg (c.8A>G) pathogenic?

HBB p.His3Arg (c.8A>G) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-17). AlphaMissense: likely benign (0.2036); Very rare (popmax 0.000257%, nfe).

How common is HBB p.His3Arg (c.8A>G) in the general population?

HBB p.His3Arg (c.8A>G) is very rare (popmax 0.000257%, nfe) (gnomAD).

What do computational predictors say about HBB p.His3Arg (c.8A>G)?

AlphaMissense predicts likely benign (score 0.2036) — an in-silico prediction, not a clinical call.

HBB p.His3Arg

c.8A>G · rs33983205 · VCV15156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2036	likely benign
REVEL	0.545	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.66, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	18.71	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 0.000257% European (non-Finnish) · 3/1,165,062 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000188% 3/1,597,836 alleles · very rare exomes 3/1,445,526 · genomes 0/152,310 · 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.His3Arg
Coding: c.8A>G
MANE Select: NM_000518
dbSNP: rs33983205
Type: single nucleotide variant
Location: chr11:5227014 (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

Similar variants

HBB p.His3= Benign ★★ same residue
HBB p.His3Pro Uncertain significance ★ ⚠ same residue
HBB p.His3Gln Likely benign ★ same residue
HBB p.His3fs Pathogenic/Likely pathogenic ★★ same residue
HBB p.His3_Leu4= Likely benign ★ same residue
HBB p.His3_Pro6delinsProGluValLysSerAlaTer Pathogenic same residue
HBB c.316-146T>G Pathogenic ★★★ same type
HBB c.316-197C>T 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-his3arg (accessed [today's date]).

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