Is ENPP5 p.Pro357Ser (c.1069C>T) pathogenic?

ENPP5 p.Pro357Ser (c.1069C>T) is classified Uncertain significance in ENPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: ambiguous (0.3916); Very rare (popmax 0.00305%, nfe).

How common is ENPP5 p.Pro357Ser (c.1069C>T) in the general population?

ENPP5 p.Pro357Ser (c.1069C>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about ENPP5 p.Pro357Ser (c.1069C>T)?

AlphaMissense predicts ambiguous (score 0.3916) — an in-silico prediction, not a clinical call.

ENPP5 p.Pro357Ser

c.1069C>T · rs369493397 · VCV2402486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3916 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3916	ambiguous
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -8.91	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 6,933 bp · p 0.26 · regional, not allelic
Overall
CADD	28.4	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 0.00305% European (non-Finnish) · 36/1,179,920 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00229% 37/1,613,596 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,776
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: ENPP5
Protein: p.Pro357Ser
Coding: c.1069C>T
MANE Select: NM_001290072
dbSNP: rs369493397
Type: single nucleotide variant
Location: chr6:46161691 (GRCh38)
Gene constraint: LOEUF 1.113 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.56 · 1 PDB

Full ENPP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP5 p.Ala270Val Uncertain significance ★ ⚠ same type
ENPP5 p.Ala402Ser Uncertain significance ★ ⚠ same type
ENPP5 p.Ala423Thr Uncertain significance ★ ⚠ same type
ENPP5 p.Asn232Thr Uncertain significance ★ ⚠ same type
ENPP5 p.Asn310Lys Uncertain significance ★ ⚠ same type
ENPP5 p.Asn338Lys Uncertain significance ★ ⚠ same type
ENPP5 p.Asn382Ser Uncertain significance ★ ⚠ same type
ENPP5 p.Asn66Asp 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/enpp5-p-pro357ser (accessed [today's date]).

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