Is MMACHC p.Pro255= (c.765C>T) pathogenic?

MMACHC p.Pro255= (c.765C>T) is classified Likely benign in MMACHC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-26). Ultra-rare (popmax 0.0332%, mid); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with MMACHC p.Pro255= (c.765C>T)?

MMACHC p.Pro255= (c.765C>T) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Pro255= (c.765C>T) in the general population?

MMACHC p.Pro255= (c.765C>T) is ultra-rare (popmax 0.0332%, mid) (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.

MMACHC p.Pro255=

c.765C>T · rs772078967 · VCV703489

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.5
Overall
CADD	4.283	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,032 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000869% 14/1,611,816 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,016
East Asian	0.00669%	14,959
African / African-American	0.004%	24,983
Remaining individualsnot grpmax-eligible	0.00321%	31,179
Admixed American	0.00167%	59,736
Finnishnot grpmax-eligible	0.00156%	63,944
European (non-Finnish)	0.00017%	589,612

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.Pro255=
Coding: c.765C>T
MANE Select: NM_015506
dbSNP: rs772078967
Type: single nucleotide variant
Location: chr1:45509131 (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 255: the 'disordered' region

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.Pro255Ala Uncertain significance ★★ ⚠ same residue
MMACHC p.Pro255Ser Uncertain significance ★★ ⚠ same residue
MMACHC p.Pro255Leu Uncertain significance ★ ⚠ same residue
MMACHC p.Pro255Thr Uncertain significance ★ ⚠ 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

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-pro255 (accessed [today's date]).

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