Is SPINT2 p.Pro111Ser (c.331C>T) pathogenic?

SPINT2 p.Pro111Ser (c.331C>T) is classified Likely benign in SPINT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0833); Rare (popmax 0.336%, nfe).

How common is SPINT2 p.Pro111Ser (c.331C>T) in the general population?

SPINT2 p.Pro111Ser (c.331C>T) is rare (popmax 0.336%, nfe) (gnomAD).

What do computational predictors say about SPINT2 p.Pro111Ser (c.331C>T)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

SPINT2 p.Pro111Ser

c.331C>T · rs141683432 · VCV1089072

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.336%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.65	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 0.15	GERP 0.66
Regional constraint	o/e 0.83	unconstrained · MANE · 27 kb · p 0.0014 · regional, not allelic
Overall
CADD	13.4	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 0.336% European (non-Finnish) · 3,959/1,179,988 alleles

Filtering AF 0.327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.323%

Overall 0.266% 4,295/1,614,130 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.336%	298
Finnishnot grpmax-eligible	0.33%	303
Remaining individualsnot grpmax-eligible	0.139%	718
African / African-American	0.0373%	2,680
Admixed American	0.015%	6,668
South Asian	0.0011%	91,086

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.Pro111Ser
Coding: c.331C>T
MANE Select: NM_021102
dbSNP: rs141683432
Type: single nucleotide variant
Location: chr19:38287929 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB
Residue 111: 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

Similar variants

SPINT2 p.Pro111= Likely benign ★ same residue
SPINT2 p.Tyr163Cys Pathogenic ★★ same type
SPINT2 p.Ala2Val Uncertain significance ★★ ⚠ same type
SPINT2 p.Ala89Val Uncertain significance ★★ ⚠ same type
SPINT2 p.Arg182Cys Uncertain significance ★★ ⚠ same type
SPINT2 p.Arg182His Uncertain significance ★★ ⚠ same type
SPINT2 p.Arg185Cys Uncertain significance ★★ ⚠ same type
SPINT2 p.Arg225Gln Uncertain significance ★★ ⚠ same type

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-pro111ser (accessed [today's date]).

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