Is NBAS p.Ser1129Phe (c.3386C>T) pathogenic?

NBAS p.Ser1129Phe (c.3386C>T) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.9137); Ultra-rare (popmax 0.0165%, mid); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.Ser1129Phe (c.3386C>T)?

NBAS p.Ser1129Phe (c.3386C>T) is associated with infantile liver failure syndrome 2, short stature-optic atrophy-Pelger-Huët anomaly syndrome (ClinVar).

How common is NBAS p.Ser1129Phe (c.3386C>T) in the general population?

NBAS p.Ser1129Phe (c.3386C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NBAS p.Ser1129Phe (c.3386C>T)?

AlphaMissense predicts likely pathogenic (score 0.9137) — an in-silico prediction, not a clinical call.

NBAS p.Ser1129Phe

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.3386C>T · rs187511292 · VCV2139145

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9137	likely pathogenic · top 5% in NBAS
REVEL	0.436	indeterminate
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	27.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000743% 12/1,614,022 alleles · ultra-rare exomes 4/1,461,770 · genomes 8/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.0117%	8,571
African / African-American	0.00533%	18,757

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.Ser1129Phe
Coding: c.3386C>T
MANE Select: NM_015909
dbSNP: rs187511292
Type: single nucleotide variant
Location: chr2:15379806 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 1129: 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

Also linked: short stature-optic atrophy-Pelger-Huët anomaly syndrome

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

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NBAS p.Ser1129= Likely benign ★ same residue
NBAS c.173-2A>G Likely pathogenic ★★ same condition
NBAS c.2423+404G>C Likely pathogenic ★★ same condition
NBAS c.335+1G>C Pathogenic/Likely pathogenic ★★ same condition
NBAS c.4583-2A>G Likely pathogenic ★★ same condition
NBAS c.513+2T>C Pathogenic/Likely pathogenic ★★ same condition
NBAS c.886-5T>A Likely pathogenic ★★ same condition
NBAS p.Arg1004Ter 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-ser1129phe (accessed [today's date]).

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