Is MECOM p.Pro351= (c.1053G>A) pathogenic?

MECOM p.Pro351= (c.1053G>A) is classified Likely benign in MECOM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-25). Ultra-rare (popmax 0.0333%, mid); Associated with Inborn genetic diseases.

What condition is associated with MECOM p.Pro351= (c.1053G>A)?

MECOM p.Pro351= (c.1053G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MECOM p.Pro351= (c.1053G>A) in the general population?

MECOM p.Pro351= (c.1053G>A) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

MECOM p.Pro351=

c.1053G>A · rs559459964 · VCV2914537

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

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 -0.68	GERP -4.7, phastCons 0.005
Overall
CADD	14.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Middle Eastern · 2/6,006 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00217% 35/1,613,590 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,003
South Asian	0.0154%	6,493
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00223%	44,868
European (non-Finnish)	0.00119%	84,272

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.Pro351=
Coding: c.1053G>A
MANE Select: NM_004991
dbSNP: rs559459964
Type: single nucleotide variant
Location: chr3:169121135 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 351: 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.Pro351Leu 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
MECOM p.Ala653Val 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-pro351 (accessed [today's date]).

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