Is ENPP2 p.Ile409Met (c.1227T>G) pathogenic?

ENPP2 p.Ile409Met (c.1227T>G) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.065); Very rare (popmax 8.49e-05%, nfe).

How common is ENPP2 p.Ile409Met (c.1227T>G) in the general population?

ENPP2 p.Ile409Met (c.1227T>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about ENPP2 p.Ile409Met (c.1227T>G)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

ENPP2 p.Ile409Met

c.1227T>G · VCV4832550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.81	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 0.049	GERP -3.6, phastCons 0.075
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	15.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,368 alleles

Overall 6.86e-05% 1/1,457,134 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: ENPP2
Protein: p.Ile409Met
Coding: c.1227T>G
MANE Select: NM_001040092
Type: single nucleotide variant
Location: chr8:119587056 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 409: an α-helix; a disulfide bond; the 'phosphodiesterase' region

Full ENPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP2 p.Arg799Trp Uncertain significance ★★ ⚠ same type
ENPP2 c.973-2122T>C Benign ★★ same type
ENPP2 c.973-2129G>A Benign ★★ same type
ENPP2 p.Arg844Cys Benign/Likely benign ★★ ⚠ same type
ENPP2 c.1781-1341A>C Uncertain significance ★ same type
ENPP2 c.973-1995C>A Uncertain significance ★ same type
ENPP2 c.973-1998C>T Uncertain significance ★ same type
ENPP2 c.973-2023G>C 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/enpp2-p-ile409met (accessed [today's date]).

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