Is ENPP2 p.Pro690Ser (c.2068C>T) pathogenic?

ENPP2 p.Pro690Ser (c.2068C>T) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely benign (0.0634); Rare (popmax 0.407%, eas).

How common is ENPP2 p.Pro690Ser (c.2068C>T) in the general population?

ENPP2 p.Pro690Ser (c.2068C>T) is rare (popmax 0.407%, eas) (gnomAD).

What do computational predictors say about ENPP2 p.Pro690Ser (c.2068C>T)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

ENPP2 p.Pro690Ser

c.2068C>T · VCV3275479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.407%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.95	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 4.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	20.2	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 0.407% East Asian · 180/44,182 alleles

Filtering AF 0.359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.34%

Overall 0.0115% 182/1,586,960 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.407%	245
Remaining individualsnot grpmax-eligible	0.00325%	30,774

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.Pro690Ser
Coding: c.2068C>T
MANE Select: NM_001040092
Type: single nucleotide variant
Location: chr8:119568238 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 690: a turn; 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-pro690ser (accessed [today's date]).

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