Is SPTB p.Trp1493Arg (c.4477T>A) pathogenic?

SPTB p.Trp1493Arg (c.4477T>A) is classified Uncertain significance in SPTB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-06). AlphaMissense: likely pathogenic (0.9622); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPTB p.Trp1493Arg (c.4477T>A)?

SPTB p.Trp1493Arg (c.4477T>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPTB p.Trp1493Arg (c.4477T>A) in the general population?

SPTB p.Trp1493Arg (c.4477T>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SPTB p.Trp1493Arg (c.4477T>A)?

AlphaMissense predicts likely pathogenic (score 0.9622) — an in-silico prediction, not a clinical call.

SPTB p.Trp1493Arg

c.4477T>A · rs1295859631 · VCV2474334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9622	likely pathogenic · top 5% in SPTB
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -12.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 46 kb · p 0.0029 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,424 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,982 alleles · very rare exomes 3/1,460,876 · genomes 1/152,106 · 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.Trp1493Arg
Coding: c.4477T>A
MANE Select: NM_001355436
dbSNP: rs1295859631
Type: single nucleotide variant
Location: chr14:64779243 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 6 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPTB p.Trp1493Ter Pathogenic/Likely pathogenic ★★ same residue
SPTB p.Ala1152Gly Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1180Thr Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1632Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1741Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1760Val Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1795Thr Uncertain significance ★★ ⚠ same condition
SPTB p.Ala1903Val Uncertain significance ★★ ⚠ 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-trp1493arg (accessed [today's date]).

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