Is MDH1 p.Asp75= (c.225C>T) pathogenic?

MDH1 p.Asp75= (c.225C>T) is classified Likely benign in MDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). Very rare (popmax 0.00308%, sas).

How common is MDH1 p.Asp75= (c.225C>T) in the general population?

MDH1 p.Asp75= (c.225C>T) is very rare (popmax 0.00308%, sas) (gnomAD).

MDH1 p.Asp75=

c.225C>T · rs748664587 · VCV2498822

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00308%, sas)

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 0.01	GERP -3.2, phastCons 0.017
Overall
CADD	6.853	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00308% South Asian · 2/64,978 alleles

Filtering AF 0.000511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000191%

Overall 0.00083% 12/1,445,188 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00308%	32,489
East Asian	0.0026%	38,518
Admixed American	0.00249%	40,218
Remaining individualsnot grpmax-eligible	0.00185%	54,186
African / African-American	0.00146%	68,698
European (non-Finnish)	0.000552%	181,308

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: MDH1
Protein: p.Asp75=
Coding: c.225C>T
MANE Select: NM_005917
dbSNP: rs748664587
Type: single nucleotide variant
Location: chr2:63597424 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 96.79 · 2 PDB
Residue 75: an α-helix

Full MDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MDH1 p.Lys66Arg Uncertain significance ★★ ⚠ same type
MDH1 c.3+295G>C Uncertain significance ★ same type
MDH1 c.3+298A>G Uncertain significance ★ same type
MDH1 p.Ala114Thr Uncertain significance ★ ⚠ same type
MDH1 p.Ala12Thr Uncertain significance ★ ⚠ same type
MDH1 p.Ala233Thr Uncertain significance ★ ⚠ same type
MDH1 p.Ala70Thr Uncertain significance ★ ⚠ same type
MDH1 p.Asn306Thr 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/mdh1-p-asp75 (accessed [today's date]).

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