Is HBB p.Ala129Val (c.386C>T) pathogenic?

HBB p.Ala129Val (c.386C>T) is classified Uncertain significance in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-17). AlphaMissense: likely benign (0.3096); Absent from gnomAD v4.1.

How common is HBB p.Ala129Val (c.386C>T) in the general population?

HBB p.Ala129Val (c.386C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Ala129Val (c.386C>T)?

AlphaMissense predicts likely benign (score 0.3096) — an in-silico prediction, not a clinical call.

HBB p.Ala129Val

c.386C>T · rs33957286 · VCV15583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3096 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3096	likely benign
REVEL	0.664	pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP 0.12
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	21.4	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.Ala129Val
Coding: c.386C>T
MANE Select: NM_000518
dbSNP: rs33957286
Type: single nucleotide variant
Location: chr11:5225656 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 129: a UniProt-annotated variant site (in j-guantanamo; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain

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

Similar variants

HBB p.Ala129Thr Uncertain significance ★★ ⚠ same residue
HBB p.Ala129Asp Uncertain significance ★ ⚠ same residue
HBB p.Ala129= Likely benign ★ 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-ala129val (accessed [today's date]).

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