Is ENPP2 p.Leu66Phe (c.196C>T) pathogenic?

ENPP2 p.Leu66Phe (c.196C>T) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: ambiguous (0.5279); Very rare (popmax 0.00593%, nfe).

How common is ENPP2 p.Leu66Phe (c.196C>T) in the general population?

ENPP2 p.Leu66Phe (c.196C>T) is very rare (popmax 0.00593%, nfe) (gnomAD).

What do computational predictors say about ENPP2 p.Leu66Phe (c.196C>T)?

AlphaMissense predicts ambiguous (score 0.5279) — an in-silico prediction, not a clinical call.

ENPP2 p.Leu66Phe

c.196C>T · rs150370902 · VCV3088978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5279 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5279	ambiguous
REVEL	0.361	indeterminate
SaProt	LLR -1.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	31.0	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 0.00593% European (non-Finnish) · 70/1,179,956 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00471% 76/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)grpmax	0.00593%	16,857
African / African-American	0.00133%	74,936
South Asian	0.0011%	91,090

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ENPP2
Protein: p.Leu66Phe
Coding: c.196C>T
MANE Select: NM_001040092
dbSNP: rs150370902
Type: single nucleotide variant
Location: chr8:119626661 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB
Residue 66: the smb 1 domain; a disulfide bond

Full ENPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP2 p.Arg799Trp Uncertain significance ★★ ⚠ same type
ENPP2 c.973-2122T>C Benign ★★ same type
ENPP2 c.973-2129G>A Benign ★★ same type
ENPP2 p.Arg844Cys Benign/Likely benign ★★ ⚠ same type
ENPP2 c.1781-1341A>C Uncertain significance ★ same type
ENPP2 c.973-1995C>A Uncertain significance ★ same type
ENPP2 c.973-1998C>T Uncertain significance ★ same type
ENPP2 c.973-2023G>C 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/enpp2-p-leu66phe (accessed [today's date]).

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