Is NBAS p.Ile984Ser (c.2951T>G) pathogenic?

NBAS p.Ile984Ser (c.2951T>G) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.8832); Very rare (popmax 0.00186%, nfe); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.Ile984Ser (c.2951T>G)?

NBAS p.Ile984Ser (c.2951T>G) is associated with infantile liver failure syndrome 2 (ClinVar).

How common is NBAS p.Ile984Ser (c.2951T>G) in the general population?

NBAS p.Ile984Ser (c.2951T>G) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about NBAS p.Ile984Ser (c.2951T>G)?

AlphaMissense predicts likely pathogenic (score 0.8832) — an in-silico prediction, not a clinical call.

NBAS p.Ile984Ser

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.2951T>G · rs140841721 · VCV1335897

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8832	likely pathogenic · top 7% in NBAS
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -13.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	26.1	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 0.00186% European (non-Finnish) · 22/1,179,624 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,613,394 alleles · very rare exomes 23/1,461,286 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,230
European (non-Finnish)grpmax	0.00186%	53,619
Admixed American	0.00167%	59,984

Remaining individuals 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.Ile984Ser
Coding: c.2951T>G
MANE Select: NM_015909
dbSNP: rs140841721
Type: single nucleotide variant
Location: chr2:15402288 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 984: 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 (in ilfs2); the 'interaction with use1' 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.Ile984fs Pathogenic/Likely pathogenic ★★ 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-ile984ser (accessed [today's date]).

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