Is CLRN1 p.Pro2= (c.6A>C) pathogenic?

CLRN1 p.Pro2= (c.6A>C) is classified Benign in CLRN1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 3.

What condition is associated with CLRN1 p.Pro2= (c.6A>C)?

CLRN1 p.Pro2= (c.6A>C) is associated with Usher syndrome type 3, Usher syndrome type 3A (ClinVar).

How is Usher syndrome inherited?

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

CLRN1 p.Pro2=

Q: How common is CLRN1 p.Pro2= (c.6A>C) in the general population?

CLRN1 p.Pro2= (c.6A>C) is common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6A>C · rs111033422 · VCV48148

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Usher syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.089	GERP 0.5, phastCons 0.97
Overall
CADD	9.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.6% African / African-American · 9,449/75,024 alleles

Filtering AF 12.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.3%

Overall 0.86% 13,887/1,614,180 alleles · common exomes 8,328/1,461,890 · genomes 5,559/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.6%	8
South Asian	2.94%	34
Remaining individualsnot grpmax-eligible	1.16%	86
Middle Eastern	1.12%	89
Admixed American	0.741%	135
Ashkenazi Jewishnot grpmax-eligible	0.149%	673
European (non-Finnish)	0.0399%	2,505
East Asian	0.00668%	14,963
Finnishnot grpmax-eligible	0.00312%	32,018

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.Pro2=
Coding: c.6A>C
MANE Select: NM_174878
dbSNP: rs111033422
Type: single nucleotide variant
Location: chr3:150972703 (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 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 3A

For Usher syndrome (Orphanet):

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

Similar variants

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
CLRN1 p.Ala123Asp Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Asn202Lys 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/clrn1-p-pro2 (accessed [today's date]).

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