Is MME p.Ser65Pro (c.193T>C) pathogenic?

MME p.Ser65Pro (c.193T>C) is classified Uncertain significance in MME (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-28). AlphaMissense: likely pathogenic (0.8877); Very rare (popmax 0.00165%, nfe); Associated with MME-related autosomal dominant Charcot Marie Tooth disease type 2.

What condition is associated with MME p.Ser65Pro (c.193T>C)?

MME p.Ser65Pro (c.193T>C) is associated with MME-related autosomal dominant Charcot Marie Tooth disease type 2 (ClinVar).

How common is MME p.Ser65Pro (c.193T>C) in the general population?

MME p.Ser65Pro (c.193T>C) is very rare (popmax 0.00165%, nfe) (gnomAD).

What do computational predictors say about MME p.Ser65Pro (c.193T>C)?

AlphaMissense predicts likely pathogenic (score 0.8877) — an in-silico prediction, not a clinical call.

MME p.Ser65Pro

Q: How is MME-related autosomal dominant Charcot Marie Tooth disease type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.193T>C · rs201910473 · VCV1676248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00165%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MME-related autosomal dominant Charcot Marie Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.8877	likely pathogenic
REVEL	0.764	pathogenic-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 96 kb · p 0.045 · regional, not allelic
Overall
CADD	23.6	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

Grpmax group 0.00165% European (non-Finnish) · 19/1,154,288 alleles

Filtering AF 0.00105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000848%

Overall 0.0012% 19/1,581,446 alleles · very rare exomes 19/1,429,138 · genomes 0/152,308 · joint denominator

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: MME
Protein: p.Ser65Pro
Coding: c.193T>C
MANE Select: NM_007289
dbSNP: rs201910473
Type: single nucleotide variant
Location: chr3:155085091 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.25 · 16 PDB
Residue 65: an α-helix; the peptidase m13 domain

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

Disease context

MME-related autosomal dominant Charcot Marie Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MME-related autosomal dominant Charcot Marie Tooth disease type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MME p.Gly579Ser Uncertain significance ★★ ⚠ same condition
MME p.Tyr507Cys Uncertain significance ★★ ⚠ same condition
MME c.1497+1G>A Likely pathogenic ★★ same type
MME c.1497+1G>C Likely pathogenic ★★ same type
MME c.160+2T>C Likely pathogenic ★★ same type
MME c.1601+2T>C Likely pathogenic ★★ same type
MME c.1781-2A>G Pathogenic/Likely pathogenic ★★ same type
MME c.439+1G>A Likely pathogenic ★★ 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/mme-p-ser65pro (accessed [today's date]).

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