Is MECOM p.Asp274= (c.822T>C) pathogenic?

MECOM p.Asp274= (c.822T>C) is classified Benign/Likely benign in MECOM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-19). Rare (popmax 0.408%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MECOM p.Asp274= (c.822T>C)?

MECOM p.Asp274= (c.822T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MECOM p.Asp274= (c.822T>C) in the general population?

MECOM p.Asp274= (c.822T>C) is rare (popmax 0.408%, nfe) (gnomAD).

MECOM p.Asp274=

c.822T>C · rs142578153 · VCV719088

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.408%, 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 1.6	GERP -4.2, phastCons 1
Overall
CADD	8.505	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.408% European (non-Finnish) · 4,808/1,179,592 alleles

Filtering AF 0.398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.394%

Overall 0.327% 5,279/1,613,646 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.769%	130
European (non-Finnish)grpmax	0.408%	245
Finnishnot grpmax-eligible	0.369%	271
Remaining individualsnot grpmax-eligible	0.214%	466
African / African-American	0.072%	1,389
Admixed American	0.0283%	3,530
South Asian	0.0242%	4,139
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

Amish 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.Asp274=
Coding: c.822T>C
MANE Select: NM_004991
dbSNP: rs142578153
Type: single nucleotide variant
Location: chr3:169127852 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 274: 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.Asp274Tyr 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-asp274 (accessed [today's date]).

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