Is HBB p.Asp22Val (c.65A>T) pathogenic?

HBB p.Asp22Val (c.65A>T) is classified Uncertain significance in HBB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-12). AlphaMissense: likely benign (0.2527); Absent from gnomAD v4.1.

How common is HBB p.Asp22Val (c.65A>T) in the general population?

HBB p.Asp22Val (c.65A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Asp22Val (c.65A>T)?

AlphaMissense predicts likely benign (score 0.2527) — an in-silico prediction, not a clinical call.

HBB p.Asp22Val

c.65A>T · rs33977536 · VCV1330078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2527 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2527	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.45	GERP 0.66, phastCons 0.002
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	19.97	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HBB
Protein: p.Asp22Val
Coding: c.65A>T
MANE Select: NM_000518
dbSNP: rs33977536
Type: single nucleotide variant
Location: chr11:5226957 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 22: an α-helix; the globin domain; a UniProt-annotated variant site (in connecticut; o(2) affinity down); a UniProt-annotated variant site (in karlskoga); a UniProt-annotated variant site (in cocody); a UniProt-annotated variant site (in yusa)

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

Similar variants

HBB p.Asp22Asn Uncertain significance ★ ⚠ same residue
HBB p.Asp22Tyr Likely benign ★ same residue
HBB p.Asp22fs 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-asp22val (accessed [today's date]).

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