Is ENPP2 p.Arg607Trp (c.1819C>T) pathogenic?

ENPP2 p.Arg607Trp (c.1819C>T) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.1806); Very rare (popmax 0.00935%, nfe).

How common is ENPP2 p.Arg607Trp (c.1819C>T) in the general population?

ENPP2 p.Arg607Trp (c.1819C>T) is very rare (popmax 0.00935%, nfe) (gnomAD).

What do computational predictors say about ENPP2 p.Arg607Trp (c.1819C>T)?

AlphaMissense predicts likely benign (score 0.1806) — an in-silico prediction, not a clinical call.

ENPP2 p.Arg607Trp

c.1819C>T · rs369390932 · VCV2390470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1806	likely benign
REVEL	0.696	pathogenic-leaning
SaProt	LLR -8.43	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.055, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	25.0	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 0.00935% European (non-Finnish) · 109/1,165,436 alleles

Filtering AF 0.00792% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00737%

Overall 0.00772% 122/1,580,114 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00935%	10,692
African / African-American	0.0082%	12,193
Remaining individualsnot grpmax-eligible	0.00817%	12,236
East Asian	0.00232%	43,132
Admixed American	0.00184%	54,358

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.Arg607Trp
Coding: c.1819C>T
MANE Select: NM_001040092
dbSNP: rs369390932
Type: single nucleotide variant
Location: chr8:119570803 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 607: a disulfide bond; the 'nuclease-like domain' 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-arg607trp (accessed [today's date]).

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