Is MME p.Pro562Ser (c.1684C>T) pathogenic?

MME p.Pro562Ser (c.1684C>T) is classified Uncertain significance in MME (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: ambiguous (0.4152); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MME p.Pro562Ser (c.1684C>T)?

MME p.Pro562Ser (c.1684C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MME p.Pro562Ser (c.1684C>T) in the general population?

MME p.Pro562Ser (c.1684C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MME p.Pro562Ser (c.1684C>T)?

AlphaMissense predicts ambiguous (score 0.4152) — an in-silico prediction, not a clinical call.

MME p.Pro562Ser

c.1684C>T · rs1334129894 · VCV2237218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4152	ambiguous
REVEL	0.659	pathogenic-leaning
SaProt	LLR -9.68	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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	26.9	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 8.48e-05% European (non-Finnish) · 1/1,179,724 alleles

Overall 0.000124% 2/1,613,682 alleles · very rare exomes 2/1,461,428 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
European (non-Finnish)grpmax	8.48e-05%	1,179,724

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro562Ser
Coding: c.1684C>T
MANE Select: NM_007289
dbSNP: rs1334129894
Type: single nucleotide variant
Location: chr3:155166925 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.25 · 16 PDB
Residue 562: the peptidase m13 domain; a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MME p.Pro562= Likely benign ★ same residue
MME p.Ala703Val Uncertain significance ★★ ⚠ same condition
MME p.Arg223Leu Uncertain significance ★★ ⚠ same condition
MME p.Arg257Gly Uncertain significance ★★ ⚠ same condition
MME p.Arg257His Uncertain significance ★★ ⚠ same condition
MME p.Arg448Gln Uncertain significance ★★ ⚠ same condition
MME p.Arg736Leu Uncertain significance ★★ ⚠ same condition
MME p.Arg748Gln Uncertain significance ★★ ⚠ 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-pro562ser (accessed [today's date]).

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