Is NBAS p.Arg137Trp (c.409C>T) pathogenic?

NBAS p.Arg137Trp (c.409C>T) is classified Pathogenic/Likely pathogenic in NBAS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-15). AlphaMissense: likely benign (0.1766); Ultra-rare (popmax 0.0493%, mid); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.Arg137Trp (c.409C>T)?

NBAS p.Arg137Trp (c.409C>T) is associated with infantile liver failure syndrome 2, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (ClinVar).

How common is NBAS p.Arg137Trp (c.409C>T) in the general population?

NBAS p.Arg137Trp (c.409C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about NBAS p.Arg137Trp (c.409C>T)?

AlphaMissense predicts likely benign (score 0.1766) — an in-silico prediction, not a clinical call.

NBAS p.Arg137Trp

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.409C>T · rs368085185 · VCV218416

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1766	likely benign ⚠ discordant with ClinVar
REVEL	0.294	indeterminate
SaProt	LLR -11.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	26.0	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 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00211% 34/1,614,042 alleles · ultra-rare exomes 32/1,461,862 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.00195%	51,306
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,914

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.Arg137Trp
Coding: c.409C>T
MANE Select: NM_015909
dbSNP: rs368085185
Type: single nucleotide variant
Location: chr2:15539327 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 137: a UniProt-annotated variant site (found in patients with a multisystem disease involving liver, eye, immune system, connective tissue and bone; likely pathogenic); 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

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

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

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NBAS p.Arg137Gln Uncertain significance ★ ⚠ same residue
NBAS p.Arg137Pro Uncertain significance ★ ⚠ same residue
NBAS c.1726-2A>G Likely pathogenic ★★ same condition
NBAS c.173-2A>G Likely pathogenic ★★ same condition
NBAS c.2423+404G>C Likely pathogenic ★★ same condition
NBAS c.4461+2T>C Likely pathogenic ★★ same condition
NBAS c.4583-2A>G Likely pathogenic ★★ same condition
NBAS c.513+2T>C Pathogenic/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-arg137trp (accessed [today's date]).

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