Is ENPP2 p.Asn353= (c.1059C>T) pathogenic?

ENPP2 p.Asn353= (c.1059C>T) is classified Likely benign in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Very rare (popmax 0.00655%, nfe).

How common is ENPP2 p.Asn353= (c.1059C>T) in the general population?

ENPP2 p.Asn353= (c.1059C>T) is very rare (popmax 0.00655%, nfe) (gnomAD).

ENPP2 p.Asn353=

c.1059C>T · rs368155133 · VCV2658779

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00655%, nfe)

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 -0.71	GERP -3.5
Overall
CADD	12.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00655% European (non-Finnish) · 77/1,176,208 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00491%

Overall 0.00522% 84/1,609,780 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00655%	15,275
Remaining individualsnot grpmax-eligible	0.00481%	20,777
African / African-American	0.00267%	37,405
East Asian	0.00223%	44,866
South Asian	0.0011%	91,008

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.Asn353=
Coding: c.1059C>T
MANE Select: NM_001040092
dbSNP: rs368155133
Type: single nucleotide variant
Location: chr8:119593774 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 353: a β-strand; 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-asn353 (accessed [today's date]).

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