Is HBB p.Ala28Val (c.83C>T) pathogenic?

HBB p.Ala28Val (c.83C>T) is classified Uncertain significance in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-24). AlphaMissense: ambiguous (0.4315); Very rare (popmax 0.00223%, eas).

How common is HBB p.Ala28Val (c.83C>T) in the general population?

HBB p.Ala28Val (c.83C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HBB p.Ala28Val (c.83C>T)?

AlphaMissense predicts ambiguous (score 0.4315) — an in-silico prediction, not a clinical call.

HBB p.Ala28Val

c.83C>T · rs33954632 · VCV15184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4315	ambiguous
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	25.2	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 0.00223% East Asian · 1/44,872 alleles

Overall 0.000124% 2/1,613,252 alleles · very rare exomes 2/1,460,980 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
South Asian	0.0011%	91,064

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.Ala28Val
Coding: c.83C>T
MANE Select: NM_000518
dbSNP: rs33954632
Type: single nucleotide variant
Location: chr11:5226939 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 28: a UniProt-annotated variant site (in volga/drenthe; unstable); a UniProt-annotated variant site (in knossos); a UniProt-annotated variant site (in grange-blanche; o(2) affinity up); an α-helix; the globin domain

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

Similar variants

HBB p.Ala28Ser Pathogenic ★★★ ⚠ same residue
HBB p.Ala28Asp Pathogenic ★ same residue
HBB p.Ala28= Likely benign ★ same residue
HBB p.Ala28Thr Likely pathogenic ⚠ same residue
HBB p.Ala28Phe Uncertain significance ★ 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

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-ala28val (accessed [today's date]).

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