Is NBAS p.Ser230fs (c.686dup) pathogenic?

NBAS p.Ser230fs (c.686dup) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-02). Ultra-rare (popmax 0.0234%, nfe); Associated with NBAS-related disorder.

What condition is associated with NBAS p.Ser230fs (c.686dup)?

NBAS p.Ser230fs (c.686dup) is associated with NBAS-related disorder, retinal disorder, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (ClinVar).

How common is NBAS p.Ser230fs (c.686dup) in the general population?

NBAS p.Ser230fs (c.686dup) is ultra-rare (popmax 0.0234%, nfe) (gnomAD).

NBAS p.Ser230fs

c.686dup · rs759315662 · VCV204581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, nfe)

Conditions

NBAS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.6	GERP 1.1, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0234% European (non-Finnish) · 276/1,179,826 alleles

Filtering AF 0.0211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0202%

Overall 0.0244% 393/1,613,722 alleles · ultra-rare exomes 339/1,461,556 · genomes 54/152,166 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.147%	681
Remaining individualsnot grpmax-eligible	0.0336%	2,975
European (non-Finnish)grpmax	0.0234%	4,275
Admixed American	0.00167%	60,010
African / African-American	0.00134%	74,904

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NBAS
Protein: p.Ser230fs
Coding: c.686dup
MANE Select: NM_015909
dbSNP: rs759315662
Type: Duplication
Location: chr2:15534602 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 230: a UniProt-annotated variant site (in ilfs2; uncertain significance); the 'interaction with use1' region

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

Disease context

NBAS-related disorder

Also linked: retinal disorder acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins short stature-optic atrophy-Pelger-Huët anomaly syndrome infantile liver failure syndrome 2

Similar variants

NBAS p.Gln1282fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Leu1231fs Pathogenic ★★ same condition
NBAS p.Leu1962fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Leu864fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Thr119fs Pathogenic ★★ same condition
NBAS p.Tyr142Ter Pathogenic/Likely pathogenic ★★ same condition
NBAS p.His940fs Likely pathogenic ★ same condition
NBAS p.Ile67fs Likely 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/nbas-p-ser230fs (accessed [today's date]).

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