Is TMPRSS15 p.Ser288Ter (c.863C>G) pathogenic?

TMPRSS15 p.Ser288Ter (c.863C>G) is classified Likely pathogenic in TMPRSS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). Very rare (popmax 0.00458%, eas); Associated with congenital enteropathy due to enteropeptidase deficiency.

What condition is associated with TMPRSS15 p.Ser288Ter (c.863C>G)?

TMPRSS15 p.Ser288Ter (c.863C>G) is associated with congenital enteropathy due to enteropeptidase deficiency (ClinVar).

How common is TMPRSS15 p.Ser288Ter (c.863C>G) in the general population?

TMPRSS15 p.Ser288Ter (c.863C>G) is very rare (popmax 0.00458%, eas) (gnomAD).

TMPRSS15 p.Ser288Ter

Q: How is Congenital enteropathy due to enteropeptidase deficiency inherited?

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

c.863C>G · VCV3780721

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00458%, eas)

Conditions

congenital enteropathy due to enteropeptidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 25
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 4.2, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00458% East Asian · 2/43,692 alleles

Filtering AF 0.000759% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000284%

Overall 0.00014% 2/1,429,168 alleles · very rare exomes 2/1,277,268 · genomes 0/151,900 · 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: TMPRSS15
Protein: p.Ser288Ter
Coding: c.863C>G
MANE Select: NM_002772
Type: single nucleotide variant
Location: chr21:18359774 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03 · 14 PDB
Residue 288: the cub 1 domain

Full TMPRSS15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital enteropathy due to enteropeptidase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital enteropathy due to enteropeptidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS15 c.1922-1G>A Likely pathogenic ★★ same condition
TMPRSS15 c.2486+1G>A Likely pathogenic ★★ same condition
TMPRSS15 p.Arg871Ter Pathogenic/Likely pathogenic ★★ same condition
TMPRSS15 p.Ser712Ter Pathogenic ★★ same condition
TMPRSS15 p.Ala491Thr Uncertain significance ★★ ⚠ same condition
TMPRSS15 p.Ser847Pro Uncertain significance ★★ ⚠ same condition
TMPRSS15 p.Tyr464Cys Uncertain significance ★★ same condition
TMPRSS15 p.Arg857Ter 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/tmprss15-p-ser288ter (accessed [today's date]).

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