Is HBB p.Val127Ala (c.380T>C) pathogenic?

HBB p.Val127Ala (c.380T>C) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-05-09). AlphaMissense: likely benign (0.1458); Ultra-rare (popmax 0.0164%, mid); Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Val127Ala (c.380T>C)?

HBB p.Val127Ala (c.380T>C) is associated with erythrocytosis, familial, 6, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Val127Ala (c.380T>C) in the general population?

HBB p.Val127Ala (c.380T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about HBB p.Val127Ala (c.380T>C)?

AlphaMissense predicts likely benign (score 0.1458) — an in-silico prediction, not a clinical call.

HBB p.Val127Ala

c.380T>C · rs33925391 · VCV15106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1458 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

erythrocytosis, familial, 6

Computational evidence

Protein change
AlphaMissense	0.1458	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -2.1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	3.533	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000744% 12/1,613,952 alleles · ultra-rare exomes 11/1,461,774 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.000254%	393,318

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.Val127Ala
Coding: c.380T>C
MANE Select: NM_000518
dbSNP: rs33925391
Type: single nucleotide variant
Location: chr11:5225662 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 127: a UniProt-annotated variant site (in beirut); a UniProt-annotated variant site (in hofu; unstable); a UniProt-annotated variant site (in b-thal; dhonburi/neapolis; unstable); an α-helix; the globin domain

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

Disease context

erythrocytosis, familial, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease beta-thalassemia HBB/LCRB hereditary persistence of fetal hemoglobin malaria, susceptibility to

Similar variants

HBB p.Val127Gly Uncertain significance ★★★ ⚠ same residue
HBB p.Val127Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Val127= Likely benign ★ same residue
HBB c.316-146T>G Pathogenic ★★★ same condition
HBB c.316-197C>T Pathogenic ★★★ same condition
HBB c.92+5G>C Pathogenic ★★★ same condition
HBB c.-78A>C Pathogenic ★★★ same condition
HBB c.*111A>G Pathogenic ★★★ same condition

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-val127ala (accessed [today's date]).

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