Is SPINT2 c.337+2T>C pathogenic?

SPINT2 c.337+2T>C is classified Pathogenic in SPINT2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-02-01). Very rare (popmax 0.000169%, nfe); Associated with congenital secretory sodium diarrhea 3.

What condition is associated with SPINT2 c.337+2T>C?

SPINT2 c.337+2T>C is associated with congenital secretory sodium diarrhea 3 (ClinVar).

How common is SPINT2 c.337+2T>C in the general population?

SPINT2 c.337+2T>C is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Congenital sodium diarrhea inherited?

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

SPINT2 c.337+2T>C

rs606231155 · VCV5206

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

congenital secretory sodium diarrhea 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.91	donor loss · deltas
Pangolin	Δ0.85	loss · gain 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Non-coding constraint	Z 2.54	1 kb window · o/e 0.79 · regional · uncalibrated
Overall
CADD	29.1	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 0.000169% European (non-Finnish) · 2/1,179,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,846 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
Coding: c.337+2T>C
MANE Select: NM_021102
dbSNP: rs606231155
Type: single nucleotide variant
Location: chr19:38287937 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB

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 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 c.553+2T>A Pathogenic same condition
SPINT2 c.593-1G>A Pathogenic same condition
SPINT2 p.Gly168Ser Pathogenic same condition
SPINT2 p.Met1Leu 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-c-337-plus-2t-c (accessed [today's date]).

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