Is MECOM p.Pro561Ser (c.1681C>T) pathogenic?

MECOM p.Pro561Ser (c.1681C>T) is classified Uncertain significance in MECOM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0796); Absent from gnomAD v4.1.

How common is MECOM p.Pro561Ser (c.1681C>T) in the general population?

MECOM p.Pro561Ser (c.1681C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MECOM p.Pro561Ser (c.1681C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

MECOM p.Pro561Ser

c.1681C>T · VCV4718474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.76, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 675 bp · p 0.034 · regional, not allelic
Overall
CADD	21.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MECOM
Protein: p.Pro561Ser
Coding: c.1681C>T
MANE Select: NM_004991
Type: single nucleotide variant
Location: chr3:169116191 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 561: the 'disordered' region

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

Similar variants

MECOM p.Pro561= Likely benign ★★ same residue
MECOM p.Pro561Arg Uncertain significance ★ ⚠ same residue
MECOM p.Arg938Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
MECOM p.Arg938Trp Pathogenic/Likely pathogenic ★★ same type
MECOM p.Thr944Ile Likely pathogenic ★★ same type
MECOM c.2577+4A>T Uncertain significance ★★ same type
MECOM c.3585+3A>G Uncertain significance ★★ same type
MECOM p.Ala1022Gly Uncertain significance ★★ ⚠ 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/mecom-p-pro561ser (accessed [today's date]).

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