Is NBAS p.Arg522His (c.1565G>A) pathogenic?

NBAS p.Arg522His (c.1565G>A) is classified Uncertain significance in NBAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-18). AlphaMissense: likely benign (0.1382); Ultra-rare (popmax 0.0165%, mid).

How common is NBAS p.Arg522His (c.1565G>A) in the general population?

NBAS p.Arg522His (c.1565G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NBAS p.Arg522His (c.1565G>A)?

AlphaMissense predicts likely benign (score 0.1382) — an in-silico prediction, not a clinical call.

NBAS p.Arg522His

c.1565G>A · rs555950436 · VCV1960559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1382 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1382	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000867% 14/1,614,180 alleles · ultra-rare exomes 10/1,461,884 · genomes 4/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00333%	30,009
African / African-American	0.00267%	37,522
European (non-Finnish)	0.000763%	131,115

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.Arg522His
Coding: c.1565G>A
MANE Select: NM_015909
dbSNP: rs555950436
Type: single nucleotide variant
Location: chr2:15474101 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 522: 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); the 'interaction with use1' region

Full NBAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NBAS p.Arg522Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
NBAS p.Arg522Leu Uncertain significance ★ same residue
NBAS p.Arg522Ser Uncertain significance ★ ⚠ same residue
NBAS c.1726-2A>G Likely pathogenic ★★ same type
NBAS c.173-2A>G Likely pathogenic ★★ same type
NBAS c.209+2T>G Pathogenic/Likely pathogenic ★★ same type
NBAS c.2423+404G>C Likely pathogenic ★★ same type
NBAS c.335+1G>C Pathogenic/Likely pathogenic ★★ same type

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-arg522his (accessed [today's date]).

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