Is NBAS p.His227Pro (c.680A>C) pathogenic?

NBAS p.His227Pro (c.680A>C) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-10-16). AlphaMissense: likely pathogenic (0.8805); Very rare (popmax 0.005%, amr); Associated with infantile liver failure syndrome 2.

What condition is associated with NBAS p.His227Pro (c.680A>C)?

NBAS p.His227Pro (c.680A>C) is associated with infantile liver failure syndrome 2 (ClinVar).

How common is NBAS p.His227Pro (c.680A>C) in the general population?

NBAS p.His227Pro (c.680A>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about NBAS p.His227Pro (c.680A>C)?

AlphaMissense predicts likely pathogenic (score 0.8805) — an in-silico prediction, not a clinical call.

NBAS p.His227Pro

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.680A>C · rs748880753 · VCV424843

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

infantile liver failure syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8805	likely pathogenic · top 7% in NBAS
REVEL	0.598	indeterminate
SaProt	LLR -12.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	25.6	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 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00031% 5/1,613,720 alleles · very rare exomes 3/1,461,546 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,002
European (non-Finnish)	0.00017%	589,894

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.His227Pro
Coding: c.680A>C
MANE Select: NM_015909
dbSNP: rs748880753
Type: single nucleotide variant
Location: chr2:15534609 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 227: a UniProt-annotated variant site (in ilfs2; uncertain significance); 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

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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
NBAS p.Arg137Trp 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-his227pro (accessed [today's date]).

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