Is SUCLA2 p.Asp263= (c.789T>C) pathogenic?

SUCLA2 p.Asp263= (c.789T>C) is classified Benign/Likely benign in SUCLA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-30). Low-frequency (popmax 1.51%, afr); Associated with mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.

How common is SUCLA2 p.Asp263= (c.789T>C) in the general population?

SUCLA2 p.Asp263= (c.789T>C) is low-frequency (popmax 1.51%, afr) (gnomAD).

SUCLA2 p.Asp263=

Q: What condition is associated with SUCLA2 p.Asp263= (c.789T>C)?

SUCLA2 p.Asp263= (c.789T>C) 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.789T>C · rs57270175 · VCV139361

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.51%, afr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.2, phastCons 1
Overall
CADD	8.742	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.51% African / African-American · 1,132/74,964 alleles

Filtering AF 1.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.41%

Overall 0.0847% 1,365/1,611,704 alleles · low-frequency exomes 739/1,459,360 · genomes 626/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.51%	66
Middle Eastern	0.339%	295
Remaining individualsnot grpmax-eligible	0.146%	685
Admixed American	0.0983%	1,017
South Asian	0.00659%	15,164
European (non-Finnish)	0.00517%	19,340
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

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.Asp263=
Coding: c.789T>C
MANE Select: NM_003850
dbSNP: rs57270175
Type: single nucleotide variant
Location: chr13:47968608 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.45 · 2 PDB
Residue 263: the atp-grasp domain

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-asp263 (accessed [today's date]).

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