Is SPINT2 p.Arg115fs (c.342del) pathogenic?

SPINT2 p.Arg115fs (c.342del) is classified Pathogenic/Likely pathogenic in SPINT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-05). Very rare (popmax 0.0011%, sas); Associated with congenital secretory sodium diarrhea 3.

What condition is associated with SPINT2 p.Arg115fs (c.342del)?

SPINT2 p.Arg115fs (c.342del) is associated with congenital secretory sodium diarrhea 3 (ClinVar).

How common is SPINT2 p.Arg115fs (c.342del) in the general population?

SPINT2 p.Arg115fs (c.342del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Congenital sodium diarrhea inherited?

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

SPINT2 p.Arg115fs

c.342del · rs1348196809 · VCV1810622

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

congenital secretory sodium diarrhea 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 0.29, phastCons 0.59

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,064 alleles

Overall 6.84e-05% 1/1,461,732 alleles · very rare

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: SPINT2
Protein: p.Arg115fs
Coding: c.342del
MANE Select: NM_021102
dbSNP: rs1348196809
Type: Deletion
Location: chr19:38289140 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB
Residue 115: a UniProt-annotated variant site (in diar3; likely pathogenic); the 'disordered' region

Full SPINT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital secretory sodium diarrhea 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital sodium diarrhea (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

SPINT2 c.593-2_593del Uncertain significance ★★ same condition
SPINT2 p.Asn57fs Pathogenic ★★ same condition
SPINT2 p.Tyr163Cys Pathogenic ★★ same condition
SPINT2 p.Arg185Cys Uncertain significance ★★ ⚠ same condition
SPINT2 p.Pro141Ala Likely pathogenic ★ ⚠ same condition
SPINT2 p.Ser41Leu Uncertain significance ★ ⚠ same condition
SPINT2 p.Tyr250fs Uncertain significance ★ same condition
SPINT2 c.337+2T>C 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/spint2-p-arg115fs (accessed [today's date]).

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