Is ENPP1 p.Ser809Phe (c.2426C>T) pathogenic?

ENPP1 p.Ser809Phe (c.2426C>T) is classified Uncertain significance in ENPP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-16). AlphaMissense: likely benign (0.1335); Very rare (popmax 0.00667%, amr); Associated with hypopigmentation-punctate palmoplantar keratoderma syndrome.

What condition is associated with ENPP1 p.Ser809Phe (c.2426C>T)?

ENPP1 p.Ser809Phe (c.2426C>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.Ser809Phe (c.2426C>T) in the general population?

ENPP1 p.Ser809Phe (c.2426C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ENPP1 p.Ser809Phe (c.2426C>T)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

ENPP1 p.Ser809Phe

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

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

c.2426C>T · VCV3593098

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypopigmentation-punctate palmoplantar keratoderma syndrome

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.1, phastCons 0.87
Regional constraint	o/e 0.82	unconstrained · MANE · 30 kb · p 8.6e-07 · regional, not allelic
Overall
CADD	18.97	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 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	8.48e-05%	1,179,906

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.Ser809Phe
Coding: c.2426C>T
MANE Select: NM_006208
Type: single nucleotide variant
Location: chr6:131885045 (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 809: the 'nuclease-like domain' region; an α-helix; a disulfide bond

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.Ser809= Likely benign ★ 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
ENPP1 p.Arg782Ter 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-ser809phe (accessed [today's date]).

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