Is SPINT2 p.Pro141Ala (c.421C>G) pathogenic?

SPINT2 p.Pro141Ala (c.421C>G) is classified Likely pathogenic in SPINT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). AlphaMissense: likely benign (0.2925); Very rare (popmax 0.000339%, nfe); Associated with congenital secretory sodium diarrhea 3.

What condition is associated with SPINT2 p.Pro141Ala (c.421C>G)?

SPINT2 p.Pro141Ala (c.421C>G) is associated with congenital secretory sodium diarrhea 3 (ClinVar).

How common is SPINT2 p.Pro141Ala (c.421C>G) in the general population?

SPINT2 p.Pro141Ala (c.421C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Congenital sodium diarrhea inherited?

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

What do computational predictors say about SPINT2 p.Pro141Ala (c.421C>G)?

AlphaMissense predicts likely benign (score 0.2925) — an in-silico prediction, not a clinical call.

SPINT2 p.Pro141Ala

c.421C>G · rs1224874674 · VCV2500740

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital secretory sodium diarrhea 3

Computational evidence

Protein change
AlphaMissense	0.2925	likely benign ⚠ discordant with ClinVar
REVEL	0.384	indeterminate
SaProt	LLR -11.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 27 kb · p 0.0014 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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) · 4/1,180,040 alleles

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

Overall 0.000248% 4/1,612,522 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.Pro141Ala
Coding: c.421C>G
MANE Select: NM_021102
dbSNP: rs1224874674
Type: single nucleotide variant
Location: chr19:38290148 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB
Residue 141: a disulfide bond; a UniProt-annotated variant site (in diar3; likely pathogenic); the bpti/kunitz inhibitor 2 domain

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.Ser41Leu Uncertain significance ★ ⚠ same condition
SPINT2 c.337+2T>C Pathogenic 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-p-pro141ala (accessed [today's date]).

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