Is MME p.Pro556Ser (c.1666C>T) pathogenic?

MME p.Pro556Ser (c.1666C>T) is classified Likely pathogenic in MME (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-08). AlphaMissense: likely pathogenic (0.9723); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2T.

What condition is associated with MME p.Pro556Ser (c.1666C>T)?

MME p.Pro556Ser (c.1666C>T) is associated with Charcot-Marie-Tooth disease axonal type 2T (ClinVar).

How common is MME p.Pro556Ser (c.1666C>T) in the general population?

MME p.Pro556Ser (c.1666C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MME p.Pro556Ser (c.1666C>T)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

MME p.Pro556Ser

c.1666C>T · rs1559961997 · VCV617584

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2T

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic ✓ concordant with ClinVar · top 10% in MME
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -11.50	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 96 kb · p 0.045 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MME
Protein: p.Pro556Ser
Coding: c.1666C>T
MANE Select: NM_007289
dbSNP: rs1559961997
Type: single nucleotide variant
Location: chr3:155166907 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.25 · 16 PDB
Residue 556: a disulfide bond; the peptidase m13 domain; a β-strand

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

Disease context

Charcot-Marie-Tooth disease axonal type 2T — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MME c.1497+1G>C Likely pathogenic ★★ same condition
MME c.1781-2A>G Pathogenic/Likely pathogenic ★★ same condition
MME c.439+1G>A Likely pathogenic ★★ same condition
MME c.536-1G>A Pathogenic/Likely pathogenic ★★ same condition
MME p.Arg448Ter Pathogenic ★★ same condition
MME p.Arg68Ter Pathogenic/Likely pathogenic ★★ same condition
MME p.Gln522Ter Pathogenic ★★ same condition
MME p.Glu280Ter Pathogenic/Likely pathogenic ★★ same condition

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/mme-p-pro556ser (accessed [today's date]).

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