Is CLRN1 p.Tyr63Ter (c.189C>A) pathogenic?

CLRN1 p.Tyr63Ter (c.189C>A) is classified Pathogenic in CLRN1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-30). Very rare (popmax 0.00667%, amr); Associated with Usher syndrome type 3A.

What condition is associated with CLRN1 p.Tyr63Ter (c.189C>A)?

CLRN1 p.Tyr63Ter (c.189C>A) is associated with Usher syndrome type 3A, retinitis pigmentosa 61, Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Tyr63Ter (c.189C>A) in the general population?

CLRN1 p.Tyr63Ter (c.189C>A) is very rare (popmax 0.00667%, amr) (gnomAD).

CLRN1 p.Tyr63Ter

c.189C>A · rs111033267 · VCV4397

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Usher syndrome type 3A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Pangolin	Δ0.28	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.85	GERP -3.7
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000991% 16/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed Americangrpmax	0.00667%	15,001
African / African-American	0.00134%	74,904
European (non-Finnish)	0.000424%	236,009

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: CLRN1
Protein: p.Tyr63Ter
Coding: c.189C>A
MANE Select: NM_174878
dbSNP: rs111033267
Type: single nucleotide variant
Location: chr3:150972520 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.74

Full CLRN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 3A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 61 Usher syndrome type 3 retinitis pigmentosa

Similar variants

CLRN1 p.Tyr63Ser Pathogenic ★★ same residue
CLRN1 p.Tyr63fs Pathogenic ★ same residue
CLRN1 p.Tyr63= Likely benign ★ same residue
CLRN1 c.253+1G>A Likely pathogenic ★★ same condition
CLRN1 c.253+6T>C Pathogenic/Likely pathogenic ★★ same condition
CLRN1 c.254-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLRN1 c.433+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLRN1 c.433+1G>T 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/clrn1-p-tyr63ter (accessed [today's date]).

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