Is MCEE p.Arg47Ter (c.139C>T) pathogenic?

MCEE p.Arg47Ter (c.139C>T) is classified Pathogenic in MCEE (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-04-16). Ultra-rare (popmax 0.0569%, nfe); Associated with MCEE-related disorders.

What condition is associated with MCEE p.Arg47Ter (c.139C>T)?

MCEE p.Arg47Ter (c.139C>T) is associated with MCEE-related disorders, methylmalonic acidemia, methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (ClinVar).

How common is MCEE p.Arg47Ter (c.139C>T) in the general population?

MCEE p.Arg47Ter (c.139C>T) is ultra-rare (popmax 0.0569%, nfe) (gnomAD).

MCEE p.Arg47Ter

c.139C>T · rs111033538 · VCV2343

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0569%, nfe)

Conditions

MCEE-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 0.69, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0569% European (non-Finnish) · 671/1,180,008 alleles

Filtering AF 0.0533% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0519%

Overall 0.0444% 717/1,613,948 alleles · ultra-rare exomes 673/1,461,832 · genomes 44/152,116 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0569%	1,759
Remaining individualsnot grpmax-eligible	0.0368%	2,717
Admixed American	0.015%	6,666
Finnishnot grpmax-eligible	0.0125%	7,999
African / African-American	0.00668%	14,980
East Asian	0.00223%	44,894

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: MCEE
Protein: p.Arg47Ter
Coding: c.139C>T
MANE Select: NM_032601
dbSNP: rs111033538
Type: single nucleotide variant
Location: chr2:71124445 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI 0.41 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.27 · 2 PDB
Residue 47: a β-strand; the voc domain

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

Disease context

MCEE-related disorders

Also linked: methylmalonic acidemia methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Similar variants

MCEE p.Arg47Leu Uncertain significance ★★ ⚠ same residue
MCEE p.Arg47Gln Uncertain significance ★ ⚠ same residue
MCEE c.379-644A>G Likely pathogenic ★★ same condition
MCEE p.Asn115Lys Uncertain significance ★★ ⚠ same condition
MCEE p.Glu174Gln Uncertain significance ★★ same condition
MCEE p.Ile159Thr Uncertain significance ★★ ⚠ same condition
MCEE p.Leu79Val Uncertain significance ★★ ⚠ same condition
MCEE p.Met1Ile 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/mcee-p-arg47ter (accessed [today's date]).

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