Is CLRN1 p.Ser146Tyr (c.437C>A) pathogenic?

CLRN1 p.Ser146Tyr (c.437C>A) is classified Likely pathogenic in CLRN1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-23). AlphaMissense: likely benign (0.3298); Very rare (popmax 6.84e-05%); Associated with Usher syndrome type 3.

What condition is associated with CLRN1 p.Ser146Tyr (c.437C>A)?

CLRN1 p.Ser146Tyr (c.437C>A) is associated with Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Ser146Tyr (c.437C>A) in the general population?

CLRN1 p.Ser146Tyr (c.437C>A) is very rare (popmax 6.84e-05%) (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.Ser146Tyr (c.437C>A)?

AlphaMissense predicts likely benign (score 0.3298) — an in-silico prediction, not a clinical call.

CLRN1 p.Ser146Tyr

c.437C>A · rs201625237 · VCV812271

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.3298	likely benign ⚠ discordant with ClinVar
REVEL	0.203	benign-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	22.4	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 6.84e-05%

Overall 6.84e-05% 1/1,461,694 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: CLRN1
Protein: p.Ser146Tyr
Coding: c.437C>A
MANE Select: NM_174878
dbSNP: rs201625237
Type: single nucleotide variant
Location: chr3:150928198 (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.Ser146Phe Uncertain significance ★★ ⚠ 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-ser146tyr (accessed [today's date]).

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