Is ENPP2 p.Arg799Trp (c.2395C>T) pathogenic?

ENPP2 p.Arg799Trp (c.2395C>T) is classified Uncertain significance in ENPP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-21). AlphaMissense: ambiguous (0.3809); Ultra-rare (popmax 0.0121%, sas).

How common is ENPP2 p.Arg799Trp (c.2395C>T) in the general population?

ENPP2 p.Arg799Trp (c.2395C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about ENPP2 p.Arg799Trp (c.2395C>T)?

AlphaMissense predicts ambiguous (score 0.3809) — an in-silico prediction, not a clinical call.

ENPP2 p.Arg799Trp

c.2395C>T · rs370024218 · VCV587542

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3809	ambiguous
REVEL	0.665	pathogenic-leaning
SaProt	LLR -11.55	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.18, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	25.6	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 0.0121% South Asian · 11/91,082 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00582% 94/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Admixed American	0.01%	9,999
East Asian	0.00668%	14,965
African / African-American	0.00667%	14,984
European (non-Finnish)	0.00559%	17,879
Remaining individualsnot grpmax-eligible	0.0048%	20,824

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.Arg799Trp
Coding: c.2395C>T
MANE Select: NM_001040092
dbSNP: rs370024218
Type: single nucleotide variant
Location: chr8:119562883 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 799: 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.Arg799Gln Uncertain significance ★ ⚠ same residue
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-arg799trp (accessed [today's date]).

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