Is ENPP7 p.Ala407Pro (c.1219G>C) pathogenic?

ENPP7 p.Ala407Pro (c.1219G>C) is classified Uncertain significance in ENPP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.0011%, sas).

How common is ENPP7 p.Ala407Pro (c.1219G>C) in the general population?

ENPP7 p.Ala407Pro (c.1219G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ENPP7 p.Ala407Pro (c.1219G>C)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

ENPP7 p.Ala407Pro

c.1219G>C · rs782048077 · VCV3089033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.09	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 -0.17	GERP -2.9
Regional constraint	o/e 0.98	unconstrained · MANE · 4,516 bp · p 0.7 · regional, not allelic
Overall
CADD	0.887	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 0.0011% South Asian · 1/90,930 alleles

Overall 6.87e-05% 1/1,456,552 alleles · very rare

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: ENPP7
Protein: p.Ala407Pro
Coding: c.1219G>C
MANE Select: NM_178543
dbSNP: rs782048077
Type: single nucleotide variant
Location: chr17:79737233 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 2 PDB
Residue 407: an α-helix

Full ENPP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP7 p.Ala174Val Uncertain significance ★ ⚠ same type
ENPP7 p.Ala231Thr Uncertain significance ★ ⚠ same type
ENPP7 p.Ala322Thr Uncertain significance ★ ⚠ same type
ENPP7 p.Ala368Thr Uncertain significance ★ ⚠ same type
ENPP7 p.Ala458Thr Uncertain significance ★ ⚠ same type
ENPP7 p.Ala5Val Uncertain significance ★ ⚠ same type
ENPP7 p.Arg156Gln Uncertain significance ★ ⚠ same type
ENPP7 p.Arg156Trp 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/enpp7-p-ala407pro (accessed [today's date]).

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