Is NDUFS2 p.Pro39= (c.117A>G) pathogenic?

NDUFS2 p.Pro39= (c.117A>G) is classified Conflicting classifications of pathogenicity in NDUFS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-04). Ultra-rare (popmax 0.0506%, afr); Associated with mitochondrial complex I deficiency, nuclear type 1.

What condition is associated with NDUFS2 p.Pro39= (c.117A>G)?

NDUFS2 p.Pro39= (c.117A>G) is associated with mitochondrial complex I deficiency, nuclear type 1 (ClinVar).

How common is NDUFS2 p.Pro39= (c.117A>G) in the general population?

NDUFS2 p.Pro39= (c.117A>G) is ultra-rare (popmax 0.0506%, afr) (gnomAD).

NDUFS2 p.Pro39=

c.117A>G · rs145578059 · VCV734528

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, afr)

Conditions

mitochondrial complex I deficiency, nuclear type 1

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 0.26	GERP -0.57, phastCons 0.32
Overall
CADD	11.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0506% African / African-American · 38/75,054 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.00322% 52/1,614,186 alleles · ultra-rare exomes 26/1,461,850 · genomes 26/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0506%	1,975
Middle Eastern	0.0331%	3,023
Admixed American	0.0167%	6,003
Remaining individualsnot grpmax-eligible	0.0032%	31,256

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: NDUFS2
Protein: p.Pro39=
Coding: c.117A>G
MANE Select: NM_001377299
dbSNP: rs145578059
Type: single nucleotide variant
Location: chr1:161203458 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.62 · 8 PDB

Full NDUFS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex I deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NDUFS2 c.-298C>G Uncertain significance ★★ same condition
NDUFS2 p.Gly33Asp Uncertain significance ★★ ⚠ same condition
NDUFS2 p.Ile456Thr Uncertain significance ★★ ⚠ same condition
NDUFS2 p.Lys404= Uncertain significance ★★ same condition
NDUFS2 c.986+12A>G Benign/Likely benign ★★ same condition
NDUFS2 c.-388G>T Benign ★★ same condition
NDUFS2 c.*114A>G Benign ★★ same condition
NDUFS2 p.Ala430= Benign ★★ 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/ndufs2-p-pro39 (accessed [today's date]).

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