Is MMUT p.Ala377Glu (c.1130C>A) pathogenic?

MMUT p.Ala377Glu (c.1130C>A) is classified Likely pathogenic in MMUT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-27). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.00267%, afr); Associated with Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency.

What condition is associated with MMUT p.Ala377Glu (c.1130C>A)?

MMUT p.Ala377Glu (c.1130C>A) is associated with Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (ClinVar).

How common is MMUT p.Ala377Glu (c.1130C>A) in the general population?

MMUT p.Ala377Glu (c.1130C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MMUT p.Ala377Glu (c.1130C>A)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

MMUT p.Ala377Glu

c.1130C>A · rs121918250 · VCV1879

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic ✓ concordant with ClinVar · top 3% in MMUT
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -17.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 28 kb · p 0.059 · regional, not allelic
Overall
CADD	29.6	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 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,832 alleles · very rare exomes 0/1,461,694 · genomes 2/152,138 · 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: MMUT
Protein: p.Ala377Glu
Coding: c.1130C>A
MANE Select: NM_000255
dbSNP: rs121918250
Type: single nucleotide variant
Location: chr6:49451668 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.72 · 6 PDB
Residue 377: a UniProt-annotated variant site (in mamm; mut-); an α-helix; a UniProt-annotated variant site (in mamm; mut0); a UniProt-annotated variant site (in mamm; mut0; decreased protein abundance; decreased methylmalonyl-coa mutase activity)

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

Disease context

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Similar variants

MMUT p.Ala377= Likely benign ★ same residue
MMUT c.1084-10A>G Pathogenic/Likely pathogenic ★★ same condition
MMUT c.1445-2A>G Pathogenic/Likely pathogenic ★★ same condition
MMUT c.1560+1G>T Pathogenic ★★ same condition
MMUT c.1677-1G>A Pathogenic ★★ same condition
MMUT c.1956+2T>C Pathogenic/Likely pathogenic ★★ same condition
MMUT c.1957-2A>G Pathogenic ★★ same condition
MMUT c.2124+1G>A Pathogenic/Likely pathogenic ★★ 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/mmut-p-ala377glu (accessed [today's date]).

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