Is SUCLA2 p.Val233= (c.699G>T) pathogenic?

SUCLA2 p.Val233= (c.699G>T) is classified Likely benign in SUCLA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-25). Very rare (popmax 0.00542%, nfe); Associated with mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.

How common is SUCLA2 p.Val233= (c.699G>T) in the general population?

SUCLA2 p.Val233= (c.699G>T) is very rare (popmax 0.00542%, nfe) (gnomAD).

SUCLA2 p.Val233=

Q: What condition is associated with SUCLA2 p.Val233= (c.699G>T)?

SUCLA2 p.Val233= (c.699G>T) is associated with mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (ClinVar).

Q: How is Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria inherited?

Typically Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

c.699G>T · rs780245301 · VCV1981776

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Conditions

mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 1.5, phastCons 1
Overall
CADD	9.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00542% European (non-Finnish) · 64/1,179,872 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00428% 69/1,612,060 alleles · very rare exomes 67/1,459,952 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,435
Admixed American	0.005%	19,991
Remaining individualsnot grpmax-eligible	0.00321%	31,160

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: SUCLA2
Protein: p.Val233=
Coding: c.699G>T
MANE Select: NM_003850
dbSNP: rs780245301
Type: single nucleotide variant
Location: chr13:47968698 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.45 · 2 PDB
Residue 233: the atp-grasp domain; an α-helix

Full SUCLA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (Orphanet):

Inheritance: Mitochondrial inheritance
Onset: Infancy

Similar variants

SUCLA2 c.534+1G>A Pathogenic ★★ same condition
SUCLA2 p.Ala307Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
SUCLA2 p.Arg160Ter Pathogenic/Likely pathogenic ★★ same condition
SUCLA2 p.Arg284Cys Pathogenic/Likely pathogenic ★★ same condition
SUCLA2 p.Asp333Gly Pathogenic/Likely pathogenic ★★ same condition
SUCLA2 p.Ala12Val Uncertain significance ★★ ⚠ same condition
SUCLA2 p.Ala27Val Uncertain significance ★★ ⚠ same condition
SUCLA2 p.Ala330Pro 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/sucla2-p-val233 (accessed [today's date]).

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