Is ENPP3 p.Met181Lys (c.542T>A) pathogenic?

ENPP3 p.Met181Lys (c.542T>A) is classified Uncertain significance in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.6332); Ultra-rare (popmax 0.0493%, eas).

How common is ENPP3 p.Met181Lys (c.542T>A) in the general population?

ENPP3 p.Met181Lys (c.542T>A) is ultra-rare (popmax 0.0493%, eas) (gnomAD).

What do computational predictors say about ENPP3 p.Met181Lys (c.542T>A)?

AlphaMissense predicts likely pathogenic (score 0.6332) — an in-silico prediction, not a clinical call.

ENPP3 p.Met181Lys

c.542T>A · VCV3275488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6332	likely pathogenic
REVEL	0.513	indeterminate
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 6.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	23.5	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 0.0493% East Asian · 22/44,626 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00172% 27/1,567,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.00492%	20,305
South Asian	0.00111%	89,982
European (non-Finnish)	8.79e-05%	1,137,826

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: ENPP3
Protein: p.Met181Lys
Coding: c.542T>A
MANE Select: NM_005021
Type: single nucleotide variant
Location: chr6:131658400 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 181: a disulfide bond; the 'phosphodiesterase' region

Full ENPP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OR2A4 p.Leu181Val Likely benign ★ ⚠ same residue
ENPP3 c.762+4T>C Likely benign ★★ same type
CTAGE9 p.Ala668Thr Uncertain significance ★ ⚠ same type
CTAGE9 p.Asp478Tyr Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu332Lys Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu414Asp Uncertain significance ★ ⚠ same type
CTAGE9 p.Ile207Thr Uncertain significance ★ ⚠ same type
ENPP3 p.Ala248Asp 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/enpp3-p-met181lys (accessed [today's date]).

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