Is ENPP4 p.Ser439Ala (c.1315T>G) pathogenic?

ENPP4 p.Ser439Ala (c.1315T>G) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely benign (0.0723); Rare (popmax 0.175%, afr).

How common is ENPP4 p.Ser439Ala (c.1315T>G) in the general population?

ENPP4 p.Ser439Ala (c.1315T>G) is rare (popmax 0.175%, afr) (gnomAD).

What do computational predictors say about ENPP4 p.Ser439Ala (c.1315T>G)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

ENPP4 p.Ser439Ala

c.1315T>G · rs16874289 · VCV2381224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.175%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.84	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 5.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,307 bp · p 0.86 · regional, not allelic
Overall
CADD	18.59	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 0.175% African / African-American · 131/74,928 alleles

Filtering AF 0.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.141%

Overall 0.00881% 142/1,612,240 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.175%	572
Middle Eastern	0.0165%	6,044
Remaining individualsnot grpmax-eligible	0.0112%	8,917
Admixed American	0.00334%	29,949
European (non-Finnish)	8.48e-05%	1,178,696

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.Ser439Ala
Coding: c.1315T>G
MANE Select: NM_014936
dbSNP: rs16874289
Type: single nucleotide variant
Location: chr6:46143593 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49 · 2 PDB
Residue 439: a UniProt-annotated variant site (in)

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-ser439ala (accessed [today's date]).

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