Is NBAS p.Ile1823Phe (c.5467A>T) pathogenic?

NBAS p.Ile1823Phe (c.5467A>T) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-23). AlphaMissense: ambiguous (0.3854); Ultra-rare (popmax 0.0934%, nfe); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.Ile1823Phe (c.5467A>T)?

NBAS p.Ile1823Phe (c.5467A>T) is associated with infantile liver failure syndrome 2 (ClinVar).

How common is NBAS p.Ile1823Phe (c.5467A>T) in the general population?

NBAS p.Ile1823Phe (c.5467A>T) is ultra-rare (popmax 0.0934%, nfe) (gnomAD).

What do computational predictors say about NBAS p.Ile1823Phe (c.5467A>T)?

AlphaMissense predicts ambiguous (score 0.3854) — an in-silico prediction, not a clinical call.

NBAS p.Ile1823Phe

Q: How is Fever-associated acute infantile liver failure syndrome inherited?

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

c.5467A>T · rs201084909 · VCV801649

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.3854	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -7.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP 0.13, phastCons 0.024
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0934% European (non-Finnish) · 1,102/1,180,034 alleles

Filtering AF 0.0888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0869%

Overall 0.0709% 1,145/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0934%	1,071
Remaining individualsnot grpmax-eligible	0.0384%	2,604
African / African-American	0.0133%	7,493
Finnishnot grpmax-eligible	0.00937%	10,671
Admixed American	0.005%	20,000

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.Ile1823Phe
Coding: c.5467A>T
MANE Select: NM_015909
dbSNP: rs201084909
Type: single nucleotide variant
Location: chr2:15275741 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 1823: 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); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance; reduced protein expression levels in fibroblasts); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance; reduced collagen secretion; diffuse collagen bundles; reduced protein expression in fibroblasts); the 'interaction with zw10 and rint1' region

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

Disease context

infantile liver failure syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fever-associated acute infantile liver failure syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NBAS p.Ile1823Val Uncertain significance ★ ⚠ same residue
NBAS c.173-2A>G Likely pathogenic ★★ same condition
NBAS c.2423+404G>C Likely pathogenic ★★ same condition
NBAS c.4583-2A>G Likely pathogenic ★★ same condition
NBAS c.513+2T>C Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Arg1004Ter Pathogenic ★★ same condition
NBAS p.Arg1236Ter Pathogenic/Likely pathogenic ★★ same condition
NBAS p.Arg136Gly 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-ile1823phe (accessed [today's date]).

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