Is ENPP6 p.Arg35Leu (c.104G>T) pathogenic?

ENPP6 p.Arg35Leu (c.104G>T) is classified Uncertain significance in ENPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely pathogenic (0.9598); Very rare (popmax 0.000763%, nfe).

How common is ENPP6 p.Arg35Leu (c.104G>T) in the general population?

ENPP6 p.Arg35Leu (c.104G>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ENPP6 p.Arg35Leu (c.104G>T)?

AlphaMissense predicts likely pathogenic (score 0.9598) — an in-silico prediction, not a clinical call.

ENPP6 p.Arg35Leu

c.104G>T · rs200037984 · VCV2236786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9598	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -13.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 127 kb · p 0.96 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000763% European (non-Finnish) · 9/1,180,030 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)grpmax	0.000763%	131,115

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: ENPP6
Protein: p.Arg35Leu
Coding: c.104G>T
MANE Select: NM_153343
dbSNP: rs200037984
Type: single nucleotide variant
Location: chr4:184217716 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06

Full ENPP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP6 p.Ser71= Benign ★★ same type
ENPP6 p.Ala20Asp Uncertain significance ★ ⚠ same type
ENPP6 p.Ala20Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala212Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala303Pro Uncertain significance ★ ⚠ same type
ENPP6 p.Ala369Gly Uncertain significance ★ ⚠ same type
ENPP6 p.Ala380Pro Uncertain significance ★ ⚠ same type
ENPP6 p.Arg181Pro 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/enpp6-p-arg35leu (accessed [today's date]).

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