Is TPRN p.Ser288Phe (c.863C>T) pathogenic?

TPRN p.Ser288Phe (c.863C>T) is classified Uncertain significance in TPRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1803); Rare (popmax 0.126%, afr); Associated with Inborn genetic diseases.

What condition is associated with TPRN p.Ser288Phe (c.863C>T)?

TPRN p.Ser288Phe (c.863C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TPRN p.Ser288Phe (c.863C>T) in the general population?

TPRN p.Ser288Phe (c.863C>T) is rare (popmax 0.126%, afr) (gnomAD).

What do computational predictors say about TPRN p.Ser288Phe (c.863C>T)?

AlphaMissense predicts likely benign (score 0.1803) — an in-silico prediction, not a clinical call.

TPRN p.Ser288Phe

c.863C>T · rs749999995 · VCV1676429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1803 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.126%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1803	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 0.96, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 8,596 bp · p 8.8e-06 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.126% African / African-American · 93/73,596 alleles

Filtering AF 0.106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0979%

Overall 0.00653% 102/1,561,146 alleles · rare exomes 64/1,409,336 · genomes 38/151,810 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.126%	791
Remaining individualsnot grpmax-eligible	0.0149%	6,714

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: TPRN
Protein: p.Ser288Phe
Coding: c.863C>T
MANE Select: NM_001128228
dbSNP: rs749999995
Type: single nucleotide variant
Location: chr9:137199849 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.27 · 1 PDB
Residue 288: the 'disordered' region

Full TPRN 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

TPRN p.Ser288Tyr Uncertain significance ★ ⚠ same residue
TPRN p.Ser288= Benign ★ same residue
TPRN p.Ala191Val Uncertain significance ★★ ⚠ same condition
TPRN p.Ala302Asp Uncertain significance ★★ ⚠ same condition
TPRN p.Arg284His Uncertain significance ★★ ⚠ same condition
TPRN p.Arg401Ser Uncertain significance ★★ ⚠ same condition
TPRN p.Arg525Gln Uncertain significance ★★ ⚠ same condition
TPRN p.Arg545Cys 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/tprn-p-ser288phe (accessed [today's date]).

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