Is MDH2 p.Pro189fs (c.566del) pathogenic?

MDH2 p.Pro189fs (c.566del) is classified Pathogenic in MDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-23). Absent from gnomAD; Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Pro189fs (c.566del)?

MDH2 p.Pro189fs (c.566del) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Pro189fs (c.566del) in the general population?

MDH2 p.Pro189fs (c.566del) is absent from gnomAD (gnomAD).

MDH2 p.Pro189fs

c.566del · rs2535869544 · VCV2231968

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.4	phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MDH2
Protein: p.Pro189fs
Coding: c.566del
MANE Select: NM_005918
dbSNP: rs2535869544
Type: Deletion
Location: chr7:76063524 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 189: an α-helix

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.Pro189Ala Uncertain significance ★★ ⚠ same residue
MDH2 p.Pro189Leu Uncertain significance ★ same residue
MDH2 c.734-3del Uncertain significance ★ same condition
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

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-pro189fs (accessed [today's date]).

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