Is SPTB p.Ser2019Phe (c.6056C>T) pathogenic?

SPTB p.Ser2019Phe (c.6056C>T) is classified Uncertain significance in SPTB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: likely benign (0.3111); Very rare (popmax 0.00102%, nfe).

How common is SPTB p.Ser2019Phe (c.6056C>T) in the general population?

SPTB p.Ser2019Phe (c.6056C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about SPTB p.Ser2019Phe (c.6056C>T)?

AlphaMissense predicts likely benign (score 0.3111) — an in-silico prediction, not a clinical call.

SPTB p.Ser2019Phe

c.6056C>T · rs775701663 · VCV2690114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3111	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP -0.99, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 46 kb · p 0.0029 · regional, not allelic
Overall
CADD	22.3	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 0.00102% European (non-Finnish) · 12/1,179,992 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,112 alleles · very rare exomes 12/1,461,796 · genomes 0/152,316 · 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.Ser2019Phe
Coding: c.6056C>T
MANE Select: NM_001355436
dbSNP: rs775701663
Type: single nucleotide variant
Location: chr14:64767826 (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

Similar variants

SPTB p.Ser2019Pro Pathogenic/Likely pathogenic ★★ same residue
SPTB c.1064+1G>A Pathogenic ★★ same type
SPTB c.1341+1G>A Likely pathogenic ★★ same type
SPTB c.3764+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTB c.474+1G>A Likely pathogenic ★★ same type
SPTB c.474+1G>T Pathogenic/Likely pathogenic ★★ same type
SPTB c.4843-1G>T Likely pathogenic ★★ same type
SPTB c.4973+5G>A Pathogenic/Likely 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/sptb-p-ser2019phe (accessed [today's date]).

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