Is ENPP1 p.Arg21Pro (c.62G>C) pathogenic?

ENPP1 p.Arg21Pro (c.62G>C) is classified Uncertain significance in ENPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: likely benign (0.0987); Very rare (popmax 0.00244%, nfe); Associated with Hypophosphataemia or rickets.

What condition is associated with ENPP1 p.Arg21Pro (c.62G>C)?

ENPP1 p.Arg21Pro (c.62G>C) is associated with Hypophosphataemia or rickets (ClinVar).

How common is ENPP1 p.Arg21Pro (c.62G>C) in the general population?

ENPP1 p.Arg21Pro (c.62G>C) is very rare (popmax 0.00244%, nfe) (gnomAD).

What do computational predictors say about ENPP1 p.Arg21Pro (c.62G>C)?

AlphaMissense predicts likely benign (score 0.0987) — an in-silico prediction, not a clinical call.

ENPP1 p.Arg21Pro

c.62G>C · VCV4683148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hypophosphataemia or rickets

Computational evidence

Protein change
AlphaMissense	0.0987	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.24	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 2.9	GERP -0.79, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 51 kb · p 0.94 · regional, not allelic
Overall
CADD	18.76	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 0.00244% European (non-Finnish) · 23/942,084 alleles

Filtering AF 0.00162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00227% 23/1,015,412 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: ENPP1
Protein: p.Arg21Pro
Coding: c.62G>C
MANE Select: NM_006208
Type: single nucleotide variant
Location: chr6:131808097 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.35 · 7 PDB
Residue 21: the 'disordered' region

Full ENPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hypophosphataemia or rickets

Similar variants

ENPP1 p.Arg21Trp Uncertain significance ★★ ⚠ same residue
ENPP1 p.Arg21= Likely benign ★ same residue
ENPP1 p.Arg782Ter Pathogenic ★★ same condition
ENPP1 p.Gly586Arg Pathogenic/Likely pathogenic ★★ same condition
ENPP1 p.Pro305Thr Pathogenic ★★ same condition
ENPP1 p.Tyr261Ter Pathogenic ★★ same condition
ENPP1 p.Tyr471Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ENPP1 p.Asp30Tyr Uncertain significance ★★ ⚠ same condition

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/enpp1-p-arg21pro (accessed [today's date]).

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