Is MMACHC p.Pro246= (c.738C>T) pathogenic?

MMACHC p.Pro246= (c.738C>T) is classified Benign in MMACHC (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.04%, afr); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MMACHC p.Pro246= (c.738C>T)?

MMACHC p.Pro246= (c.738C>T) is associated with Disorders of Intracellular Cobalamin Metabolism, methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Pro246= (c.738C>T) in the general population?

MMACHC p.Pro246= (c.738C>T) is low-frequency (popmax 4.04%, afr) (gnomAD).

MMACHC p.Pro246=

c.738C>T · rs16832550 · VCV138239

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.04%, afr)

Conditions

Disorders of Intracellular Cobalamin Metabolism

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 0.29	GERP -3.3
Overall
CADD	0.689	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.04% African / African-American · 3,023/74,918 alleles

Filtering AF 3.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.87%

Overall 0.322% 5,187/1,612,282 alleles · low-frequency exomes 3,276/1,460,042 · genomes 1,911/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.04%	25
Ashkenazi Jewishnot grpmax-eligible	2.33%	43
Middle Eastern	1.34%	75
Remaining individualsnot grpmax-eligible	0.594%	168
Admixed American	0.499%	200
South Asian	0.111%	900
European (non-Finnish)	0.0533%	1,878

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.Pro246=
Coding: c.738C>T
MANE Select: NM_015506
dbSNP: rs16832550
Type: single nucleotide variant
Location: chr1:45509104 (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 246: the 'disordered' region

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

Disease context

Disorders of Intracellular Cobalamin Metabolism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylmalonic aciduria and homocystinuria type cblC

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-pro246 (accessed [today's date]).

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