Is MDH2 p.Ser16Arg (c.48C>G) pathogenic?

MDH2 p.Ser16Arg (c.48C>G) is classified Uncertain significance in MDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: ambiguous (0.421); Very rare (popmax 8.72e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MDH2 p.Ser16Arg (c.48C>G)?

MDH2 p.Ser16Arg (c.48C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MDH2 p.Ser16Arg (c.48C>G) in the general population?

MDH2 p.Ser16Arg (c.48C>G) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about MDH2 p.Ser16Arg (c.48C>G)?

AlphaMissense predicts ambiguous (score 0.421) — an in-silico prediction, not a clinical call.

MDH2 p.Ser16Arg

c.48C>G · rs1209100286 · VCV1743933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.421	ambiguous
REVEL	0.04	moderately benign-leaning
SaProt	LLR -10.15	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.54 · regional, not allelic
Overall
CADD	22.9	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 8.72e-05% European (non-Finnish) · 1/1,146,758 alleles

Overall 7.23e-05% 1/1,383,662 alleles · very rare

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.Ser16Arg
Coding: c.48C>G
MANE Select: NM_005918
dbSNP: rs1209100286
Type: single nucleotide variant
Location: chr7:76048208 (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.Ser16Gly Uncertain significance ★★ ⚠ same residue
MDH2 p.Ser16= Likely benign ★★ same residue
MDH2 p.Ser16Ile 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

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-ser16arg (accessed [today's date]).

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