Is ARSG p.Lys222fs (c.663_664del) pathogenic?

ARSG p.Lys222fs (c.663664del) is classified Conflicting classifications of pathogenicity in ARSG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-25). Very rare (popmax 0.000169%, nfe); Associated with Usher syndrome, type 4.

What condition is associated with ARSG p.Lys222fs (c.663_664del)?

ARSG p.Lys222fs (c.663_664del) is associated with Usher syndrome, type 4 (ClinVar).

How common is ARSG p.Lys222fs (c.663_664del) in the general population?

ARSG p.Lys222fs (c.663_664del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ARSG p.Lys222fs

c.663_664del · rs923958450 · VCV2412753

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Usher syndrome, type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.86	GERP 0.51

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000169%	590,016

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARSG
Protein: p.Lys222fs
Coding: c.663_664del
MANE Select: NM_001267727
dbSNP: rs923958450
Type: Deletion
Location: chr17:68356762 (GRCh38)
Gene constraint: LOEUF 0.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90

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

Disease context

Usher syndrome, type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

ARSG c.983-2_983-1del Pathogenic/Likely pathogenic ★★ same condition
ARSG p.Ser443fs Pathogenic/Likely pathogenic ★★ same condition
ARSG c.566+3_566+8del Conflicting classifications of pathogenicity ★ same condition
SLC16A6 p.Ala222Val Likely benign ★ same residue
ARSG c.705-3940_982+2952del Pathogenic same condition
ARSG c.1092-5C>T Benign/Likely benign ★★ same condition
ARSG p.Pro255= Benign ★★ same condition
ARSG p.Thr236Ser Benign ★★ 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/arsg-p-lys222fs (accessed [today's date]).

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