Is ENPP5 p.Ala402Ser (c.1204G>T) pathogenic?

ENPP5 p.Ala402Ser (c.1204G>T) is classified Uncertain significance in ENPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.012%, afr).

How common is ENPP5 p.Ala402Ser (c.1204G>T) in the general population?

ENPP5 p.Ala402Ser (c.1204G>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about ENPP5 p.Ala402Ser (c.1204G>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

ENPP5 p.Ala402Ser

c.1204G>T · VCV4664406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -4.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -5.3
Regional constraint	o/e 0.95	unconstrained · MANE · 6,933 bp · p 0.26 · regional, not allelic
Overall
CADD	0.794	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.012% African / African-American · 9/74,914 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000558% 9/1,613,838 alleles · ultra-rare

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.Ala402Ser
Coding: c.1204G>T
MANE Select: NM_001290072
Type: single nucleotide variant
Location: chr6:46161556 (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.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
ENPP5 p.Gln254His 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-ala402ser (accessed [today's date]).

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