Is CLRN1 p.Phe18Leu (c.52T>C) pathogenic?

CLRN1 p.Phe18Leu (c.52T>C) is classified Uncertain significance in CLRN1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-30). AlphaMissense: ambiguous (0.3625); Absent from gnomAD v4.1; Associated with Usher syndrome type 3.

What condition is associated with CLRN1 p.Phe18Leu (c.52T>C)?

CLRN1 p.Phe18Leu (c.52T>C) is associated with Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Phe18Leu (c.52T>C) in the general population?

CLRN1 p.Phe18Leu (c.52T>C) is absent from gnomAD v4.1 (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 CLRN1 p.Phe18Leu (c.52T>C)?

AlphaMissense predicts ambiguous (score 0.3625) — an in-silico prediction, not a clinical call.

CLRN1 p.Phe18Leu

c.52T>C · VCV4064861

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3625 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Usher syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.3625	ambiguous
REVEL	0.307	indeterminate
SaProt	LLR -4.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.53, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	19.24	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLRN1
Protein: p.Phe18Leu
Coding: c.52T>C
MANE Select: NM_174878
Type: single nucleotide variant
Location: chr3:150972657 (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

For Usher syndrome (Orphanet):

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

Similar variants

CLRN1 p.Phe18= Likely benign ★ same residue
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.Asn48Lys 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-phe18leu (accessed [today's date]).

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