Is NFU1 p.Pro233= (c.699G>A) pathogenic?

NFU1 p.Pro233= (c.699G>A) is classified Benign/Likely benign in NFU1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-09). Ultra-rare (popmax 0.0111%, eas); Associated with multiple mitochondrial dysfunctions syndrome 1.

What condition is associated with NFU1 p.Pro233= (c.699G>A)?

NFU1 p.Pro233= (c.699G>A) is associated with multiple mitochondrial dysfunctions syndrome 1 (ClinVar).

How common is NFU1 p.Pro233= (c.699G>A) in the general population?

NFU1 p.Pro233= (c.699G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

NFU1 p.Pro233=

Q: How is Multiple mitochondrial dysfunctions syndrome type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.699G>A · rs200732109 · VCV1229286

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

multiple mitochondrial dysfunctions syndrome 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 -1.3	GERP -3.4, phastCons 0.001
Overall
CADD	10.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,888 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00124% 20/1,613,914 alleles · ultra-rare exomes 18/1,461,784 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,978
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,826
African / African-American	0.00133%	74,910
European (non-Finnish)	0.000593%	168,565

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: NFU1
Protein: p.Pro233=
Coding: c.699G>A
MANE Select: NM_001002755
dbSNP: rs200732109
Type: single nucleotide variant
Location: chr2:69400385 (GRCh38)
Gene constraint: LOEUF 1.544 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.07 · 2 PDB
Residue 233: the 'nifu' region

Full NFU1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple mitochondrial dysfunctions syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple mitochondrial dysfunctions syndrome type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

NFU1 p.Pro233Leu Uncertain significance ★★ ⚠ same residue
NFU1 p.Pro233Thr Uncertain significance ★★ ⚠ same residue
NFU1 c.303-2A>T Likely pathogenic ★★ same condition
NFU1 c.545+5G>A Pathogenic ★★ same condition
NFU1 c.62+89G>A Pathogenic/Likely pathogenic ★★ same condition
NFU1 p.Arg182Gln Pathogenic/Likely pathogenic ★★ same condition
NFU1 p.Arg182Trp Pathogenic ★★ same condition
NFU1 p.Gly208Cys Pathogenic ★★ 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/nfu1-p-pro233 (accessed [today's date]).

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