Is MMUT p.Pro615Arg (c.1844C>G) pathogenic?

MMUT p.Pro615Arg (c.1844C>G) is classified Uncertain significance in MMUT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-12-28). AlphaMissense: likely pathogenic (0.995); Absent from gnomAD v4.1; Associated with methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency.

What condition is associated with MMUT p.Pro615Arg (c.1844C>G)?

MMUT p.Pro615Arg (c.1844C>G) is associated with methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (ClinVar).

How common is MMUT p.Pro615Arg (c.1844C>G) in the general population?

MMUT p.Pro615Arg (c.1844C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MMUT p.Pro615Arg (c.1844C>G)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

MMUT p.Pro615Arg

Q: How is Vitamin B12-unresponsive methylmalonic acidemia inherited?

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

c.1844C>G · rs1554158777 · VCV550276

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 8% in MMUT
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -16.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 28 kb · p 0.059 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MMUT
Protein: p.Pro615Arg
Coding: c.1844C>G
MANE Select: NM_000255
dbSNP: rs1554158777
Type: single nucleotide variant
Location: chr6:49440318 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.72 · 6 PDB
Residue 615: a UniProt-annotated variant site (in mamm; mut0; affects proper folding; reduced strongly protein level); a UniProt-annotated variant site (in mamm; mut0); a UniProt-annotated variant site (in mamm; mut0; affects proper folding; reduced strongly protein level; loss of methylmalonyl-coa mutase activity); a UniProt-annotated variant site (in mamm; mut-); the b12-binding domain

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

Disease context

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

For Vitamin B12-unresponsive methylmalonic acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

MMUT p.Pro615Leu Pathogenic ★★ same residue
MMUT p.Pro615Thr Pathogenic ★★ same residue
MMUT c.1084-10A>G Pathogenic/Likely pathogenic ★★ same condition
MMUT c.1084-2A>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.1677-1G>C 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-pro615arg (accessed [today's date]).

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