Is ENPP4 p.Met152Arg (c.455T>G) pathogenic?

ENPP4 p.Met152Arg (c.455T>G) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: likely benign (0.1983); Absent from gnomAD v4.1.

How common is ENPP4 p.Met152Arg (c.455T>G) in the general population?

ENPP4 p.Met152Arg (c.455T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENPP4 p.Met152Arg (c.455T>G)?

AlphaMissense predicts likely benign (score 0.1983) — an in-silico prediction, not a clinical call.

ENPP4 p.Met152Arg

c.455T>G · VCV3508638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1983	likely benign
REVEL	0.523	indeterminate
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Pangolin	Δ0.49	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 706 bp · p 0.0047 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENPP4
Protein: p.Met152Arg
Coding: c.455T>G
MANE Select: NM_014936
Type: single nucleotide variant
Location: chr6:46140038 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49 · 2 PDB

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-met152arg (accessed [today's date]).

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