Is MCEE p.Val13Ala (c.38T>C) pathogenic?

MCEE p.Val13Ala (c.38T>C) is classified Uncertain significance in MCEE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0535); Ultra-rare (popmax 0.0671%, amr); Associated with methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency.

What condition is associated with MCEE p.Val13Ala (c.38T>C)?

MCEE p.Val13Ala (c.38T>C) is associated with methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (ClinVar).

How common is MCEE p.Val13Ala (c.38T>C) in the general population?

MCEE p.Val13Ala (c.38T>C) is ultra-rare (popmax 0.0671%, amr) (gnomAD).

What do computational predictors say about MCEE p.Val13Ala (c.38T>C)?

AlphaMissense predicts likely benign (score 0.0535) — an in-silico prediction, not a clinical call.

MCEE p.Val13Ala

Q: How is Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.38T>C · rs746939893 · VCV2081936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0671%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Computational evidence

Protein change
AlphaMissense	0.0535	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.45	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.13	GERP -1.6
Regional constraint	o/e 1.01	unconstrained · MANE · 20 kb · p 0.9 · regional, not allelic
Overall
CADD	0.36	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 0.0671% Admixed American · 40/59,610 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00249% 40/1,609,012 alleles · ultra-rare exomes 39/1,456,846 · genomes 1/152,166 · joint denominator

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.Val13Ala
Coding: c.38T>C
MANE Select: NM_032601
dbSNP: rs746939893
Type: single nucleotide variant
Location: chr2:71130182 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI 0.41 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.27 · 2 PDB

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

Disease context

methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MCEE c.379-644A>G Likely pathogenic ★★ same condition
MCEE p.Arg47Ter Pathogenic ★★ same condition
MCEE p.Arg47Leu Uncertain significance ★★ ⚠ 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-val13ala (accessed [today's date]).

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