Is MMADHC p.Val274= (c.822A>G) pathogenic?

MMADHC p.Val274= (c.822A>G) is classified Likely benign in MMADHC (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-09). Very rare (popmax 0.00133%, afr); Associated with methylmalonic aciduria and homocystinuria type cblD.

What condition is associated with MMADHC p.Val274= (c.822A>G)?

MMADHC p.Val274= (c.822A>G) is associated with methylmalonic aciduria and homocystinuria type cblD (ClinVar).

How common is MMADHC p.Val274= (c.822A>G) in the general population?

MMADHC p.Val274= (c.822A>G) is very rare (popmax 0.00133%, 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.

MMADHC p.Val274=

c.822A>G · rs1474967244 · VCV1118278

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

methylmalonic aciduria and homocystinuria type cblD

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 -0.54	GERP -2.9
Overall
CADD	7.147	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,016 alleles

Overall 6.2e-05% 1/1,613,720 alleles · very rare exomes 1/1,461,484 · genomes 0/152,236 · joint denominator

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: MMADHC
Protein: p.Val274=
Coding: c.822A>G
MANE Select: NM_015702
dbSNP: rs1474967244
Type: single nucleotide variant
Location: chr2:149570043 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67 · 4 PDB
Residue 274: a UniProt-annotated variant site (in macd); a β-strand; a UniProt-annotated variant site (in mahcd)

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

Disease context

methylmalonic aciduria and homocystinuria type cblD — 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

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MMADHC c.154+1G>A Pathogenic/Likely pathogenic ★★ same condition
MMADHC c.610-1G>A Likely pathogenic ★★ same condition
MMADHC p.Arg158Ter Pathogenic ★★ same condition
MMADHC p.Arg216Ter Pathogenic/Likely pathogenic ★★ same condition
MMADHC p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
MMADHC p.Gln180Ter 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/mmadhc-p-val274 (accessed [today's date]).

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