Is ENPP6 p.Ser71Leu (c.212C>T) pathogenic?

ENPP6 p.Ser71Leu (c.212C>T) is classified Uncertain significance in ENPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.9903); Very rare (popmax 0.00667%, afr).

How common is ENPP6 p.Ser71Leu (c.212C>T) in the general population?

ENPP6 p.Ser71Leu (c.212C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ENPP6 p.Ser71Leu (c.212C>T)?

AlphaMissense predicts likely pathogenic (score 0.9903) — an in-silico prediction, not a clinical call.

ENPP6 p.Ser71Leu

c.212C>T · VCV4018161

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9903	likely pathogenic · top 3% in ENPP6
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -11.38	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 127 kb · p 0.96 · regional, not allelic
Overall
CADD	33.0	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 0.00667% African / African-American · 5/74,950 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000805% 13/1,614,114 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,990
European (non-Finnish)	0.000678%	147,505

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.Ser71Leu
Coding: c.212C>T
MANE Select: NM_153343
Type: single nucleotide variant
Location: chr4:184217608 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06
Residue 71: a modified residue (phosphoserine); an active site; a binding site

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

Similar variants

ENPP6 p.Ser71= Benign ★★ same residue
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-ser71leu (accessed [today's date]).

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