Is MDH2 p.Ile148Phe (c.442A>T) pathogenic?

MDH2 p.Ile148Phe (c.442A>T) is classified Uncertain significance in MDH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.8726); Ultra-rare (popmax 0.0307%, afr); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Ile148Phe (c.442A>T)?

MDH2 p.Ile148Phe (c.442A>T) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Ile148Phe (c.442A>T) in the general population?

MDH2 p.Ile148Phe (c.442A>T) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about MDH2 p.Ile148Phe (c.442A>T)?

AlphaMissense predicts likely pathogenic (score 0.8726) — an in-silico prediction, not a clinical call.

MDH2 p.Ile148Phe

c.442A>T · rs375411208 · VCV1379043

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8726	likely pathogenic
REVEL	0.399	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	acceptor loss, 12 bp away · masked 0 · deltas
Pangolin	Δ0.41	loss · gain 0.38 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.1	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.54 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% African / African-American · 23/74,918 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00161% 26/1,614,014 alleles · ultra-rare exomes 11/1,461,856 · genomes 15/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,257
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,474
South Asian	0.0011%	91,090

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.Ile148Phe
Coding: c.442A>T
MANE Select: NM_005918
dbSNP: rs375411208
Type: single nucleotide variant
Location: chr7:76060385 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.49 · 7 PDB
Residue 148: 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.Ile148Met 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-ile148phe (accessed [today's date]).

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