Is ENPP7 p.Arg59Gln (c.176G>A) pathogenic?

ENPP7 p.Arg59Gln (c.176G>A) is classified Likely benign in ENPP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0706); Very rare (popmax 0.00892%, eas).

How common is ENPP7 p.Arg59Gln (c.176G>A) in the general population?

ENPP7 p.Arg59Gln (c.176G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about ENPP7 p.Arg59Gln (c.176G>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

ENPP7 p.Arg59Gln

c.176G>A · VCV4018178

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -9.41	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 -5.2	GERP -4.2
Regional constraint	o/e 0.76	unconstrained · MANE · 232 bp · p 0.013 · regional, not allelic
Overall
CADD	0.115	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 0.00892% East Asian · 4/44,866 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00235% 38/1,613,866 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
Admixed American	0.00667%	15,002
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
European (non-Finnish)	0.00237%	42,141
South Asian	0.0011%	91,072

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.Arg59Gln
Coding: c.176G>A
MANE Select: NM_178543
Type: single nucleotide variant
Location: chr17:79731315 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 2 PDB
Residue 59: 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-arg59gln (accessed [today's date]).

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