Is ENPP3 p.Ala248Asp (c.743C>A) pathogenic?

ENPP3 p.Ala248Asp (c.743C>A) is classified Uncertain significance in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.1115); Absent from gnomAD v4.1.

How common is ENPP3 p.Ala248Asp (c.743C>A) in the general population?

ENPP3 p.Ala248Asp (c.743C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENPP3 p.Ala248Asp (c.743C>A)?

AlphaMissense predicts likely benign (score 0.1115) — an in-silico prediction, not a clinical call.

ENPP3 p.Ala248Asp

c.743C>A · VCV3844983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1115 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1115	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -5.80	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 -1	GERP -1
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	13.81	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: ENPP3
Protein: p.Ala248Asp
Coding: c.743C>A
MANE Select: NM_005021
Type: single nucleotide variant
Location: chr6:131674262 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 248: a disulfide bond; the 'phosphodiesterase' region; an α-helix

Full ENPP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP3 c.762+4T>C Likely benign ★★ same type
CTAGE9 p.Ala668Thr Uncertain significance ★ ⚠ same type
CTAGE9 p.Asp478Tyr Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu332Lys Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu414Asp Uncertain significance ★ ⚠ same type
CTAGE9 p.Ile207Thr Uncertain significance ★ ⚠ same type
ENPP3 p.Ala330Pro Uncertain significance ★ ⚠ same type
ENPP3 p.Ala371Val 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/enpp3-p-ala248asp (accessed [today's date]).

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