Is MMACHC p.Pro3Arg (c.8C>G) pathogenic?

MMACHC p.Pro3Arg (c.8C>G) is classified Conflicting classifications of pathogenicity in MMACHC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-16). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.04%, afr); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with MMACHC p.Pro3Arg (c.8C>G)?

MMACHC p.Pro3Arg (c.8C>G) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Pro3Arg (c.8C>G) in the general population?

MMACHC p.Pro3Arg (c.8C>G) is ultra-rare (popmax 0.04%, afr) (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.Pro3Arg (c.8C>G)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

MMACHC p.Pro3Arg

c.8C>G · rs201807738 · VCV1545615

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.38	indeterminate
SaProt	LLR -8.84	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 1.4	GERP 0.83, phastCons 0.18
Regional constraint	o/e 1.08	unconstrained · MANE · 8,879 bp · p 0.15 · regional, not allelic
Overall
CADD	15.87	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 0.04% African / African-American · 30/74,912 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00719% 116/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,497
Admixed American	0.0233%	4,286
Remaining individualsnot grpmax-eligible	0.0176%	5,679
European (non-Finnish)	0.00517%	19,345

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.Pro3Arg
Coding: c.8C>G
MANE Select: NM_015506
dbSNP: rs201807738
Type: single nucleotide variant
Location: chr1:45500340 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 7 PDB
Residue 3: an α-helix

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 p.Pro3= Likely benign ★ same residue
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

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-pro3arg (accessed [today's date]).

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