Is ENPP1 p.Pro72Ser (c.214C>T) pathogenic?

ENPP1 p.Pro72Ser (c.214C>T) is classified Uncertain significance in ENPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1422); Very rare (popmax 0.00132%); Associated with hypophosphatemic rickets, autosomal recessive, 2.

What condition is associated with ENPP1 p.Pro72Ser (c.214C>T)?

ENPP1 p.Pro72Ser (c.214C>T) is associated with hypophosphatemic rickets, autosomal recessive, 2, arterial calcification, generalized, of infancy, 1 (ClinVar).

How common is ENPP1 p.Pro72Ser (c.214C>T) in the general population?

ENPP1 p.Pro72Ser (c.214C>T) is very rare (popmax 0.00132%) (gnomAD).

How is Autosomal recessive hypophosphatemic rickets inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ENPP1 p.Pro72Ser (c.214C>T)?

AlphaMissense predicts likely benign (score 0.1422) — an in-silico prediction, not a clinical call.

ENPP1 p.Pro72Ser

c.214C>T · rs1475050245 · VCV906279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00132%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatemic rickets, autosomal recessive, 2

Computational evidence

Protein change
AlphaMissense	0.1422	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -5.59	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 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 51 kb · p 0.94 · regional, not allelic
Overall
CADD	24.2	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 0.00132%

Overall 0.00132% 2/152,082 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.Pro72Ser
Coding: c.214C>T
MANE Select: NM_006208
dbSNP: rs1475050245
Type: single nucleotide variant
Location: chr6:131808249 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.35 · 7 PDB

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

Disease context

hypophosphatemic rickets, autosomal recessive, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arterial calcification, generalized, of infancy, 1

For Autosomal recessive hypophosphatemic rickets (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ENPP1 c.2230+1G>A Pathogenic ★★ same condition
ENPP1 c.2608-1G>A Likely pathogenic ★★ same condition
ENPP1 c.313+1G>A Pathogenic/Likely pathogenic ★★ same condition
ENPP1 p.Arg456Ter Pathogenic/Likely pathogenic ★★ same condition
ENPP1 p.Arg476Ter Pathogenic ★★ same condition
ENPP1 p.Arg481Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ENPP1 p.Arg782Ter Pathogenic ★★ same condition
ENPP1 p.Glu866Lys Likely pathogenic ★★ 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-pro72ser (accessed [today's date]).

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