Is HBB p.Ala14Val (c.41C>T) pathogenic?

HBB p.Ala14Val (c.41C>T) is classified Uncertain significance in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-02). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00187%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Ala14Val (c.41C>T)?

HBB p.Ala14Val (c.41C>T) is associated with beta thalassemia (ClinVar).

How common is HBB p.Ala14Val (c.41C>T) in the general population?

HBB p.Ala14Val (c.41C>T) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about HBB p.Ala14Val (c.41C>T)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

HBB p.Ala14Val

c.41C>T · rs35203747 · VCV619858

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

beta thalassemia

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -10.44	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	0.61	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 0.00187% European (non-Finnish) · 22/1,179,440 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,613,376 alleles · very rare exomes 20/1,461,188 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,611
African / African-American	0.00134%	74,894

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.Ala14Val
Coding: c.41C>T
MANE Select: NM_000518
dbSNP: rs35203747
Type: single nucleotide variant
Location: chr11:5226981 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 14: an α-helix; the globin domain; a UniProt-annotated variant site (in j-lens)

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

Disease context

beta thalassemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HBB p.Ala14Thr Uncertain significance ★ ⚠ 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
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same condition
HBB p.Lys18Ter 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-ala14val (accessed [today's date]).

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