Is MDH2 p.Pro149= (c.447C>T) pathogenic?

MDH2 p.Pro149= (c.447C>T) is classified Likely benign in MDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-30). Absent from gnomAD v4.1.

How common is MDH2 p.Pro149= (c.447C>T) in the general population?

MDH2 p.Pro149= (c.447C>T) is absent from gnomAD v4.1 (gnomAD).

MDH2 p.Pro149=

c.447C>T · rs2535863742 · VCV2750122

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Pangolin	Δ0.31	loss · gain 0.29 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -2.1
Overall
CADD	4.8	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.Pro149=
Coding: c.447C>T
MANE Select: NM_005918
dbSNP: rs2535863742
Type: single nucleotide variant
Location: chr7:76060390 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 149: an α-helix

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

Similar variants

MDH2 p.Pro149Arg Uncertain significance ★ ⚠ same residue
MDH2 p.Pro149Leu Uncertain significance ★ ⚠ same residue
MDH2 p.Pro133Leu Pathogenic/Likely pathogenic ★★ same type
MDH2 c.555+3A>G Uncertain significance ★★ same type
MDH2 p.Ala126Thr Uncertain significance ★★ ⚠ same type
MDH2 p.Ala135Gly Uncertain significance ★★ ⚠ same type
MDH2 p.Ala141Thr Uncertain significance ★★ same type
MDH2 p.Ala177Thr Uncertain significance ★★ ⚠ same type

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-pro149 (accessed [today's date]).

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