Is ENPP1 p.Pro20Ser (c.58C>T) pathogenic?

ENPP1 p.Pro20Ser (c.58C>T) is classified Uncertain significance in ENPP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.0704); Very rare (popmax 0.000861%, nfe); Associated with hypopigmentation-punctate palmoplantar keratoderma syndrome.

What condition is associated with ENPP1 p.Pro20Ser (c.58C>T)?

ENPP1 p.Pro20Ser (c.58C>T) is associated with hypopigmentation-punctate palmoplantar keratoderma syndrome, type 2 diabetes mellitus, arterial calcification, generalized, of infancy, 1 (ClinVar).

How common is ENPP1 p.Pro20Ser (c.58C>T) in the general population?

ENPP1 p.Pro20Ser (c.58C>T) is very rare (popmax 0.000861%, nfe) (gnomAD).

What do computational predictors say about ENPP1 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

ENPP1 p.Pro20Ser

Q: How is Hypopigmentation-punctate palmoplantar keratoderma syndrome inherited?

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

c.58C>T · rs926768412 · VCV2876863

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000861%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypopigmentation-punctate palmoplantar keratoderma syndrome

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.40	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 -2.4	GERP -1.2
Regional constraint	o/e 1.00	unconstrained · MANE · 51 kb · p 0.94 · regional, not allelic
Overall
CADD	9.84	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 0.000861% European (non-Finnish) · 8/928,752 alleles

Filtering AF 0.000371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000268%

Overall 0.000805% 8/993,758 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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_006208
dbSNP: rs926768412
Type: single nucleotide variant
Location: chr6:131808093 (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 20: the 'disordered' region

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

Disease context

hypopigmentation-punctate palmoplantar keratoderma syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus arterial calcification, generalized, of infancy, 1 hypophosphatemic rickets, autosomal recessive, 2 inherited obesity

For Hypopigmentation-punctate palmoplantar keratoderma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ENPP1 p.Pro20= Likely benign ★★ same residue
ENPP1 p.Pro20Leu Uncertain significance ★ ⚠ same residue
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

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-pro20ser (accessed [today's date]).

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