Is NBAS p.Ile512fs (c.1533_1545del) pathogenic?

NBAS p.Ile512fs (c.15331545del) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00667%, amr); Associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome.

What condition is associated with NBAS p.Ile512fs (c.1533_1545del)?

NBAS p.Ile512fs (c.1533_1545del) is associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, infantile liver failure syndrome 2 (ClinVar).

How common is NBAS p.Ile512fs (c.1533_1545del) in the general population?

NBAS p.Ile512fs (c.1533_1545del) is very rare (popmax 0.00667%, amr) (gnomAD).

NBAS p.Ile512fs

c.1533_1545del · rs775395168 · VCV1457999

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

short stature-optic atrophy-Pelger-Huët anomaly syndrome

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 15 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, 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 0.00667% Admixed American · 4/60,006 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00291% 47/1,614,100 alleles · very rare exomes 46/1,461,888 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	0.00364%	27,443

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.Ile512fs
Coding: c.1533_1545del
MANE Select: NM_015909
dbSNP: rs775395168
Type: Deletion
Location: chr2:15474121 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 512: a UniProt-annotated variant site (in ilfs2; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance); the 'interaction with use1' region

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

Disease context

short stature-optic atrophy-Pelger-Huët anomaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins infantile liver failure syndrome 2

Similar variants

NBAS p.Asp2149_Ile2150insTer Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Ile984fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Leu1507fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Leu1726fs Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Phe167fs Pathogenic ★★ same condition
NBAS p.Ser1419fs Pathogenic ★★ same condition
NBAS p.Trp1850fs Pathogenic ★★ same condition
NBAS c.4657_4659+18del 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-ile512fs (accessed [today's date]).

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