Is MDH2 p.Pro219= (c.657C>T) pathogenic?

MDH2 p.Pro219= (c.657C>T) is classified Likely benign in MDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-04). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Pro219= (c.657C>T)?

MDH2 p.Pro219= (c.657C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Pro219= (c.657C>T) in the general population?

MDH2 p.Pro219= (c.657C>T) is absent from gnomAD v4.1 (gnomAD).

MDH2 p.Pro219=

c.657C>T · rs1798035716 · VCV2017083

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -0.21	phastCons 0.25
Overall
CADD	10.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MDH2
Protein: p.Pro219=
Coding: c.657C>T
MANE Select: NM_005918
dbSNP: rs1798035716
Type: single nucleotide variant
Location: chr7:76064362 (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.Pro219Arg 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
MDH2 p.Ala325Val 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-pro219 (accessed [today's date]).

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