Is ENPP4 p.Pro267Leu (c.800C>T) pathogenic?

ENPP4 p.Pro267Leu (c.800C>T) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.6997); Absent from gnomAD v4.1.

How common is ENPP4 p.Pro267Leu (c.800C>T) in the general population?

ENPP4 p.Pro267Leu (c.800C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENPP4 p.Pro267Leu (c.800C>T)?

AlphaMissense predicts likely pathogenic (score 0.6997) — an in-silico prediction, not a clinical call.

ENPP4 p.Pro267Leu

c.800C>T · VCV4664395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6997 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,583,034)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6997	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -10.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,307 bp · p 0.86 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,583,034). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ENPP4
Protein: p.Pro267Leu
Coding: c.800C>T
MANE Select: NM_014936
Type: single nucleotide variant
Location: chr6:46140383 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49 · 2 PDB
Residue 267: a disulfide bond; a β-strand

Full ENPP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP4 p.Ala181Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Glu Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Gly Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Ser Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Val Uncertain significance ★ ⚠ same type
ENPP4 p.Ala90Ser 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/enpp4-p-pro267leu (accessed [today's date]).

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