Is NBAS p.Ser544fs (c.1628_1629insA) pathogenic?

NBAS p.Ser544fs (c.16281629insA) is classified Pathogenic in NBAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). Very rare (popmax 0.000339%, nfe); Associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins.

What condition is associated with NBAS p.Ser544fs (c.1628_1629insA)?

NBAS p.Ser544fs (c.1628_1629insA) is associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (ClinVar).

How common is NBAS p.Ser544fs (c.1628_1629insA) in the general population?

NBAS p.Ser544fs (c.1628_1629insA) is very rare (popmax 0.000339%, nfe) (gnomAD).

NBAS p.Ser544fs

Q: How is Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins inherited?

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

c.1628_1629insA · rs1680038424 · VCV1406108

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

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 16 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Overall
CADD	34.0	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 0.000339% European (non-Finnish) · 4/1,179,892 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,872 alleles · very rare exomes 3/1,461,696 · genomes 1/152,176 · joint denominator

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.Ser544fs
Coding: c.1628_1629insA
MANE Select: NM_015909
dbSNP: rs1680038424
Type: Insertion
Location: chr2:15473318 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 544: 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

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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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-ser544fs (accessed [today's date]).

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