Is ARSG p.Leu92Pro (c.275T>C) pathogenic?

ARSG p.Leu92Pro (c.275T>C) is classified Pathogenic in ARSG (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.9648); Very rare (popmax 0.000424%, nfe); Associated with Usher syndrome, type 4.

What condition is associated with ARSG p.Leu92Pro (c.275T>C)?

ARSG p.Leu92Pro (c.275T>C) is associated with Usher syndrome, type 4 (ClinVar).

How common is ARSG p.Leu92Pro (c.275T>C) in the general population?

ARSG p.Leu92Pro (c.275T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Usher syndrome inherited?

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

What do computational predictors say about ARSG p.Leu92Pro (c.275T>C)?

AlphaMissense predicts likely pathogenic (score 0.9648) — an in-silico prediction, not a clinical call.

ARSG p.Leu92Pro

c.275T>C · rs200685916 · VCV2576531

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome, type 4

Computational evidence

Protein change
AlphaMissense	0.9648	likely pathogenic ✓ concordant with ClinVar · top 3% in ARSG
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -16.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 113 kb · p 0.075 · regional, not allelic
Overall
CADD	28.5	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 0.000424% European (non-Finnish) · 5/1,179,966 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,776 alleles · very rare

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.Leu92Pro
Coding: c.275T>C
MANE Select: NM_001267727
dbSNP: rs200685916
Type: single nucleotide variant
Location: chr17:68343660 (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.1092-5C>T Benign/Likely benign ★★ same condition
ARSG p.Pro255= Benign ★★ same condition
ARSG p.Thr236Ser Benign ★★ same condition
ARSG p.Trp274Arg Benign ★★ same condition
ARSG c.407-2A>C Likely pathogenic ★ same condition
ARSG c.982+1G>C Likely pathogenic ★ same condition
ARSG p.Trp274Ter Likely pathogenic ★ same condition
ARSG p.Arg342Trp Uncertain significance ★ ⚠ 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-leu92pro (accessed [today's date]).

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