Is SPTB p.Ser2019Pro (c.6055T>C) pathogenic?

SPTB p.Ser2019Pro (c.6055T>C) is classified Pathogenic/Likely pathogenic in SPTB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.9389); Very rare (popmax 6.2e-05%); Associated with hereditary spherocytosis type 2.

What condition is associated with SPTB p.Ser2019Pro (c.6055T>C)?

SPTB p.Ser2019Pro (c.6055T>C) is associated with hereditary spherocytosis type 2, elliptocytosis 3 (ClinVar).

How common is SPTB p.Ser2019Pro (c.6055T>C) in the general population?

SPTB p.Ser2019Pro (c.6055T>C) is very rare (popmax 6.2e-05%) (gnomAD).

How is Hereditary spherocytosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SPTB p.Ser2019Pro (c.6055T>C)?

AlphaMissense predicts likely pathogenic (score 0.9389) — an in-silico prediction, not a clinical call.

SPTB p.Ser2019Pro

c.6055T>C · rs121918648 · VCV12837

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spherocytosis type 2

Computational evidence

Protein change
AlphaMissense	0.9389	likely pathogenic ✓ concordant with ClinVar · top 7% in SPTB
REVEL	0.301	indeterminate
SaProt	LLR -12.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP -0.58, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 46 kb · p 0.0029 · 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

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,042 alleles · very rare exomes 1/1,461,794 · genomes 0/152,248 · joint denominator

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: SPTB
Protein: p.Ser2019Pro
Coding: c.6055T>C
MANE Select: NM_001355436
dbSNP: rs121918648
Type: single nucleotide variant
Location: chr14:64767827 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 6 PDB
Residue 2019: a UniProt-annotated variant site (in el3; providence); an α-helix

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

Disease context

hereditary spherocytosis type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: elliptocytosis 3

For Hereditary spherocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Germany)

Similar variants

SPTB p.Ser2019Phe Uncertain significance ★ ⚠ same residue
SPTB c.3764+1G>A Pathogenic/Likely pathogenic ★★ same condition
SPTB c.474+1G>A Likely pathogenic ★★ same condition
SPTB c.4973+5G>A Pathogenic/Likely pathogenic ★★ same condition
SPTB c.5178+1G>A Likely pathogenic ★★ same condition
SPTB c.647+1G>A Likely pathogenic ★★ same condition
SPTB p.Arg1306Ter Pathogenic/Likely pathogenic ★★ same condition
SPTB p.Arg1423Ter Pathogenic/Likely 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/sptb-p-ser2019pro (accessed [today's date]).

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