Is MMACHC p.Pro46Arg (c.137C>G) pathogenic?

MMACHC p.Pro46Arg (c.137C>G) is classified Uncertain significance in MMACHC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-20). AlphaMissense: likely benign (0.1196); Very rare (popmax 0.000254%, nfe); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with MMACHC p.Pro46Arg (c.137C>G)?

MMACHC p.Pro46Arg (c.137C>G) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Pro46Arg (c.137C>G) in the general population?

MMACHC p.Pro46Arg (c.137C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Methylmalonic acidemia with homocystinuria inherited?

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

What do computational predictors say about MMACHC p.Pro46Arg (c.137C>G)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

MMACHC p.Pro46Arg

c.137C>G · rs2149323209 · VCV1419294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 8,879 bp · p 0.15 · regional, not allelic
Overall
CADD	23.9	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 0.000254% European (non-Finnish) · 3/1,180,026 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,888 alleles · very rare

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: MMACHC
Protein: p.Pro46Arg
Coding: c.137C>G
MANE Select: NM_015506
dbSNP: rs2149323209
Type: single nucleotide variant
Location: chr1:45507411 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 7 PDB

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

Disease context

methylmalonic aciduria and homocystinuria type cblC — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Methylmalonic acidemia with homocystinuria (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

MMACHC c.430-1G>A Likely pathogenic ★★ same condition
MMACHC c.430-2A>G Likely pathogenic ★★ same condition
MMACHC c.81+1G>A Pathogenic ★★ same condition
MMACHC c.81+1G>C Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.81+2T>G Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.82-1G>A Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.82-2A>G Pathogenic/Likely pathogenic ★★ same condition
MMACHC p.Ala117Pro 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/mmachc-p-pro46arg (accessed [today's date]).

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