Is ME1 p.Pro554Ser (c.1660C>T) pathogenic?

ME1 p.Pro554Ser (c.1660C>T) is classified Uncertain significance in ME1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1917); Very rare (popmax 0.000509%, nfe).

How common is ME1 p.Pro554Ser (c.1660C>T) in the general population?

ME1 p.Pro554Ser (c.1660C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about ME1 p.Pro554Ser (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.1917) — an in-silico prediction, not a clinical call.

ME1 p.Pro554Ser

c.1660C>T · VCV4105655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1917	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.45	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 9.7	GERP 2.5, phastCons 1
Overall
CADD	20.7	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 0.000509% European (non-Finnish) · 6/1,177,806 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,458,188 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: ME1
Protein: p.Pro554Ser
Coding: c.1660C>T
MANE Select: NM_020957 · reported on NM_002395
Type: single nucleotide variant
Location: chr6:83211983 (GRCh38)
Structure: AlphaFold pLDDT 82.84
Residue 554: the cadherin 5 domain

Full ME1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCDHB16 p.Val301Leu Uncertain significance ★★ same type
ME1 p.Ala302Thr Uncertain significance ★ ⚠ same type
ME1 p.Ala310Val Uncertain significance ★ ⚠ same type
ME1 p.Ala467Ser Uncertain significance ★ ⚠ same type
ME1 p.Arg118Gln Uncertain significance ★ ⚠ same type
ME1 p.Arg155Leu Uncertain significance ★ ⚠ same type
ME1 p.Arg212Gln Uncertain significance ★ ⚠ same type
ME1 p.Arg254Cys 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/me1-p-pro554ser (accessed [today's date]).

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