Is ME2 p.Pro514Ser (c.1540C>T) pathogenic?

ME2 p.Pro514Ser (c.1540C>T) is classified Uncertain significance in ME2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.8834); Very rare (popmax 0.00111%, sas).

How common is ME2 p.Pro514Ser (c.1540C>T) in the general population?

ME2 p.Pro514Ser (c.1540C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about ME2 p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts likely pathogenic (score 0.8834) — an in-silico prediction, not a clinical call.

ME2 p.Pro514Ser

c.1540C>T · VCV4053021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8834	likely pathogenic
REVEL	0.752	pathogenic-leaning
SaProt	LLR -12.56	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 2, phastCons 1
Overall
CADD	27.5	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 0.00111% South Asian · 1/90,144 alleles

Overall 6.85e-05% 1/1,459,138 alleles · very 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: ME2
Protein: p.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_001378328 · reported on NM_002396
Type: single nucleotide variant
Location: chr18:50940339 (GRCh38)
Residue 514: a UniProt-annotated variant site (in lmphm9); the cadherin 3 domain

Full ME2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR1 p.Ala2442Val Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala2955Thr Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala396Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala617Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1323Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1379His Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1720Trp 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/me2-p-pro514ser (accessed [today's date]).

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