Is ENPP2 p.Phe28Leu (c.82T>C) pathogenic?

ENPP2 p.Phe28Leu (c.82T>C) is classified Uncertain significance in ENPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.6121); Very rare (popmax 0.01%, amr).

How common is ENPP2 p.Phe28Leu (c.82T>C) in the general population?

ENPP2 p.Phe28Leu (c.82T>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ENPP2 p.Phe28Leu (c.82T>C)?

AlphaMissense predicts likely pathogenic (score 0.6121) — an in-silico prediction, not a clinical call.

ENPP2 p.Phe28Leu

c.82T>C · VCV3508615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6121	likely pathogenic
REVEL	0.188	benign-leaning
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.59, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 81 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	21.0	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 0.01% Admixed American · 6/60,012 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00391% 63/1,611,232 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.00801%	12,481
European (non-Finnish)	0.00416%	24,029
Finnishnot grpmax-eligible	0.00312%	32,019
African / African-American	0.00134%	74,886

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.Phe28Leu
Coding: c.82T>C
MANE Select: NM_001040092
Type: single nucleotide variant
Location: chr8:119638479 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 91.61 · 9 PDB

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-phe28leu (accessed [today's date]).

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