Is MECOM p.Pro195= (c.585C>T) pathogenic?

MECOM p.Pro195= (c.585C>T) is classified Conflicting classifications of pathogenicity in MECOM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-14). Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MECOM p.Pro195= (c.585C>T)?

MECOM p.Pro195= (c.585C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MECOM p.Pro195= (c.585C>T) in the general population?

MECOM p.Pro195= (c.585C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MECOM p.Pro195=

c.585C>T · VCV4105844

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.6, phastCons 1
Overall
CADD	7.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,988 alleles

Overall 0.000805% 13/1,613,994 alleles · very rare exomes 10/1,461,742 · genomes 3/152,252 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,819
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	8.47e-05%	1,179,988

Finnish 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: MECOM
Protein: p.Pro195=
Coding: c.585C>T
MANE Select: NM_004991
Type: single nucleotide variant
Location: chr3:169131457 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 195: the 'interaction with mapk9, smad3 and probably suv39h1' region

Full MECOM 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

MECOM p.Pro195Ser Uncertain significance ★ ⚠ same residue
MECOM p.Pro195Thr Uncertain significance ★ ⚠ same residue
MECOM p.Ala1022Gly Uncertain significance ★★ ⚠ same condition
MECOM p.Ala1228Val Uncertain significance ★★ ⚠ same condition
MECOM p.Ala222Val Uncertain significance ★★ ⚠ same condition
MECOM p.Ala434Val Uncertain significance ★★ ⚠ same condition
MECOM p.Ala477Gly Uncertain significance ★★ ⚠ same condition
MECOM p.Ala537Thr 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/mecom-p-pro195 (accessed [today's date]).

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