Is ENPP7 p.Arg217Trp (c.649C>T) pathogenic?

ENPP7 p.Arg217Trp (c.649C>T) is classified Uncertain significance in ENPP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.1356); Very rare (popmax 0.00333%, amr).

How common is ENPP7 p.Arg217Trp (c.649C>T) in the general population?

ENPP7 p.Arg217Trp (c.649C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ENPP7 p.Arg217Trp (c.649C>T)?

AlphaMissense predicts likely benign (score 0.1356) — an in-silico prediction, not a clinical call.

ENPP7 p.Arg217Trp

c.649C>T · rs781807069 · VCV3089041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1356	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.9	GERP -4.4
Regional constraint	o/e 0.98	unconstrained · MANE · 4,516 bp · p 0.7 · regional, not allelic
Overall
CADD	19.48	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000682% 11/1,613,196 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
South Asian	0.00329%	30,360
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000424%	236,005

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.Arg217Trp
Coding: c.649C>T
MANE Select: NM_178543
dbSNP: rs781807069
Type: single nucleotide variant
Location: chr17:79735292 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 2 PDB
Residue 217: 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.Ala407Pro 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

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-arg217trp (accessed [today's date]).

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