Is MCEE p.Ala76Val (c.227C>T) pathogenic?

MCEE p.Ala76Val (c.227C>T) is classified Benign in MCEE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1051); Common (popmax 37.8%, mid) — too common for a highly-penetrant pathogenic allele; Associated with methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency.

What condition is associated with MCEE p.Ala76Val (c.227C>T)?

MCEE p.Ala76Val (c.227C>T) is associated with methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (ClinVar).

What do computational predictors say about MCEE p.Ala76Val (c.227C>T)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

MCEE p.Ala76Val

Q: How common is MCEE p.Ala76Val (c.227C>T) in the general population?

MCEE p.Ala76Val (c.227C>T) is common (popmax 37.8%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.227C>T · rs11541017 · VCV138182

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 37.8%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -4.72	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 -1.6	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 20 kb · p 0.9 · regional, not allelic
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.8% Middle Eastern · 2,294/6,062 alleles

Filtering AF 36.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.3%

Overall 33.7% 543,131/1,613,590 alleles · common exomes 502,377/1,461,524 · genomes 40,754/152,066 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	42.6%	2
Finnishnot grpmax-eligible	40.8%	2
Middle Easterngrpmax	37.8%	3
European (non-Finnish)	36.5%	3
Remaining individualsnot grpmax-eligible	32.7%	3
South Asian	30.2%	3
Amishnot grpmax-eligible	28.5%	4
Admixed American	26%	4
African / African-American	7.33%	14
East Asian	6.03%	17

Ashkenazi Jewish 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: MCEE
Protein: p.Ala76Val
Coding: c.227C>T
MANE Select: NM_032601
dbSNP: rs11541017
Type: single nucleotide variant
Location: chr2:71124357 (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 76: an α-helix; the voc domain; a UniProt-annotated variant site (in)

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 p.Ala76= Likely benign ★ same residue
MCEE p.Ala76Met Uncertain significance ★ same residue
MCEE p.Ala76Thr Uncertain significance ★ ⚠ same residue
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

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-ala76val (accessed [today's date]).

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