Is SPINT2 p.Cys158= (c.474C>T) pathogenic?

SPINT2 p.Cys158= (c.474C>T) is classified Likely benign in SPINT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). Ultra-rare (popmax 0.0132%, sas).

How common is SPINT2 p.Cys158= (c.474C>T) in the general population?

SPINT2 p.Cys158= (c.474C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

SPINT2 p.Cys158=

c.474C>T · rs1255750053 · VCV1614493

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -5.2
Overall
CADD	4.959	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,010 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000744% 12/1,612,570 alleles · ultra-rare exomes 12/1,460,240 · genomes 0/152,330 · 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: SPINT2
Protein: p.Cys158=
Coding: c.474C>T
MANE Select: NM_021102
dbSNP: rs1255750053
Type: single nucleotide variant
Location: chr19:38290201 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 1 PDB
Residue 158: 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

Similar variants

SPINT2 p.Cys158Tyr Uncertain significance ★ ⚠ 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-cys158 (accessed [today's date]).

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