Is ENPP4 p.Ile147Leu (c.439A>C) pathogenic?

ENPP4 p.Ile147Leu (c.439A>C) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely benign (0.0819); Very rare (popmax 0.00802%, afr).

How common is ENPP4 p.Ile147Leu (c.439A>C) in the general population?

ENPP4 p.Ile147Leu (c.439A>C) is very rare (popmax 0.00802%, afr) (gnomAD).

What do computational predictors say about ENPP4 p.Ile147Leu (c.439A>C)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

ENPP4 p.Ile147Leu

c.439A>C · rs144828075 · VCV2374742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -4.81	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 8.1	GERP -1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 706 bp · p 0.0047 · regional, not allelic
Overall
CADD	13.36	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 0.00802% African / African-American · 6/74,802 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000434% 7/1,612,616 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,467
Remaining individualsnot grpmax-eligible	0.0016%	62,426

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: ENPP4
Protein: p.Ile147Leu
Coding: c.439A>C
MANE Select: NM_014936
dbSNP: rs144828075
Type: single nucleotide variant
Location: chr6:46140022 (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-ile147leu (accessed [today's date]).

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