Is ENPP6 p.Arg181Pro (c.542G>C) pathogenic?

ENPP6 p.Arg181Pro (c.542G>C) is classified Uncertain significance in ENPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.5468); Ultra-rare (popmax 0.0853%, afr).

How common is ENPP6 p.Arg181Pro (c.542G>C) in the general population?

ENPP6 p.Arg181Pro (c.542G>C) is ultra-rare (popmax 0.0853%, afr) (gnomAD).

What do computational predictors say about ENPP6 p.Arg181Pro (c.542G>C)?

AlphaMissense predicts ambiguous (score 0.5468) — an in-silico prediction, not a clinical call.

ENPP6 p.Arg181Pro

c.542G>C · VCV4249247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5468 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0853%, afr)

Computational evidence

Protein change
AlphaMissense	0.5468	ambiguous
REVEL	0.462	indeterminate
SaProt	LLR -11.58	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -0.036, phastCons 0.09
Regional constraint	o/e 1.00	unconstrained · MANE · 127 kb · p 0.96 · regional, not allelic
Overall
CADD	15.83	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 0.0853% African / African-American · 64/75,038 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0624%

Overall 0.00465% 75/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0853%	1,172
Remaining individualsnot grpmax-eligible	0.0096%	10,416
Admixed American	0.00833%	12,003

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: ENPP6
Protein: p.Arg181Pro
Coding: c.542G>C
MANE Select: NM_153343
Type: single nucleotide variant
Location: chr4:184117892 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06

Full ENPP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP6 p.Arg181Trp Uncertain significance ★ ⚠ same residue
ENPP6 p.Ser71= Benign ★★ same type
ENPP6 p.Ala20Asp Uncertain significance ★ ⚠ same type
ENPP6 p.Ala20Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala212Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala303Pro Uncertain significance ★ ⚠ same type
ENPP6 p.Ala369Gly Uncertain significance ★ ⚠ same type
ENPP6 p.Ala380Pro 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/enpp6-p-arg181pro (accessed [today's date]).

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