Is SPINT2 p.Met1Val (c.1A>G) pathogenic?

SPINT2 p.Met1Val (c.1A>G) is classified Pathogenic in SPINT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-23). Very rare (popmax 0.00245%, eas).

How common is SPINT2 p.Met1Val (c.1A>G) in the general population?

SPINT2 p.Met1Val (c.1A>G) is very rare (popmax 0.00245%, eas) (gnomAD).

SPINT2 p.Met1Val

c.1A>G · VCV3611761

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00245%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.307	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.5, phastCons 1
Overall
CADD	19.82	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 0.00245% East Asian · 1/40,838 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000217% 3/1,381,980 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00245%	40,838
European (non-Finnish)	0.000175%	572,849

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.Met1Val
Coding: c.1A>G
MANE Select: NM_021102
Type: single nucleotide variant
Location: chr19:38264893 (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

Similar variants

SPINT2 p.Met1Ile Pathogenic ★ same residue
SPINT2 p.Met1Leu Pathogenic 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

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-met1val (accessed [today's date]).

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