Is MECOM p.Pro809Ser (c.2425C>T) pathogenic?

MECOM p.Pro809Ser (c.2425C>T) is classified Uncertain significance in MECOM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.074); Ultra-rare (popmax 0.0231%, sas); Associated with Inborn genetic diseases.

What condition is associated with MECOM p.Pro809Ser (c.2425C>T)?

MECOM p.Pro809Ser (c.2425C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MECOM p.Pro809Ser (c.2425C>T) in the general population?

MECOM p.Pro809Ser (c.2425C>T) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about MECOM p.Pro809Ser (c.2425C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

MECOM p.Pro809Ser

c.2425C>T · VCV3871800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.049	GERP -2.3, phastCons 0.51
Regional constraint	o/e 1.09	unconstrained · MANE · 14 kb · p 0.12 · regional, not allelic
Overall
CADD	4.686	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,080 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00167% 27/1,614,044 alleles · ultra-rare exomes 26/1,461,860 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,337
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000339%	295,011

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.Pro809Ser
Coding: c.2425C>T
MANE Select: NM_004991
Type: single nucleotide variant
Location: chr3:169115447 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 809: the 'disordered' 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.Pro809Leu Uncertain significance ★★ ⚠ same residue
MECOM p.Pro809= Likely benign ★ 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-pro809ser (accessed [today's date]).

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