Is NBAS p.Glu997Ala (c.2990A>C) pathogenic?

NBAS p.Glu997Ala (c.2990A>C) is classified Benign/Likely benign in NBAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1571); Low-frequency (popmax 1.15%, sas); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.Glu997Ala (c.2990A>C)?

NBAS p.Glu997Ala (c.2990A>C) is associated with infantile liver failure syndrome 2, short stature-optic atrophy-Pelger-Huët anomaly syndrome (ClinVar).

How common is NBAS p.Glu997Ala (c.2990A>C) in the general population?

NBAS p.Glu997Ala (c.2990A>C) is low-frequency (popmax 1.15%, sas) (gnomAD).

What do computational predictors say about NBAS p.Glu997Ala (c.2990A>C)?

AlphaMissense predicts likely benign (score 0.1571) — an in-silico prediction, not a clinical call.

NBAS p.Glu997Ala

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.2990A>C · rs538592084 · VCV1167816

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1571 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.15%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1571	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	21.5	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 1.15% South Asian · 1,046/91,076 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.07%

Overall 0.0682% 1,101/1,613,648 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.15%	87
Remaining individualsnot grpmax-eligible	0.0592%	1,689
East Asian	0.00223%	44,780
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00136%	73,729

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.Glu997Ala
Coding: c.2990A>C
MANE Select: NM_015909
dbSNP: rs538592084
Type: single nucleotide variant
Location: chr2:15402249 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 997: 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); 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: 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.Glu997Gln Uncertain significance ★ ⚠ 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-glu997ala (accessed [today's date]).

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