Is MDH2 p.Pro48= (c.144C>A) pathogenic?

MDH2 p.Pro48= (c.144C>A) is classified Likely benign in MDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-23). Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Pro48= (c.144C>A)?

MDH2 p.Pro48= (c.144C>A) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Pro48= (c.144C>A) in the general population?

MDH2 p.Pro48= (c.144C>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

MDH2 p.Pro48=

c.144C>A · rs1282385392 · VCV1772883

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

Inborn genetic diseases

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 -0.12	phastCons 0.001
Overall
CADD	8.823	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,996 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00118% 19/1,614,044 alleles · ultra-rare exomes 10/1,461,886 · genomes 9/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,333
African / African-American	0.00133%	74,928

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: MDH2
Protein: p.Pro48=
Coding: c.144C>A
MANE Select: NM_005918
dbSNP: rs1282385392
Type: single nucleotide variant
Location: chr7:76054907 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB

Full MDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MDH2 p.Pro48Leu Uncertain significance ★ same residue
MDH2 p.Pro48Ser Uncertain significance ★ ⚠ same residue
MDH2 p.Ala135Gly Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala141Thr Uncertain significance ★★ same condition
MDH2 p.Ala177Thr Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala242Val Uncertain significance ★★ ⚠ same condition
MDH2 p.Ala256Thr Uncertain significance ★★ ⚠ 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/mdh2-p-pro48 (accessed [today's date]).

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