Is CLRN1 p.Ile168Phe (c.502A>T) pathogenic?

CLRN1 p.Ile168Phe (c.502A>T) is classified Conflicting classifications of pathogenicity in CLRN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-27). AlphaMissense: ambiguous (0.3958); Very rare (popmax 0.000509%, nfe); Associated with CLRN1-related disorder.

What condition is associated with CLRN1 p.Ile168Phe (c.502A>T)?

CLRN1 p.Ile168Phe (c.502A>T) is associated with CLRN1-related disorder, Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Ile168Phe (c.502A>T) in the general population?

CLRN1 p.Ile168Phe (c.502A>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CLRN1 p.Ile168Phe (c.502A>T)?

AlphaMissense predicts ambiguous (score 0.3958) — an in-silico prediction, not a clinical call.

CLRN1 p.Ile168Phe

c.502A>T · rs780412161 · VCV899882

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CLRN1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3958	ambiguous
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -8.95	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	25.2	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 0.000509% European (non-Finnish) · 6/1,179,916 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,416 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.Ile168Phe
Coding: c.502A>T
MANE Select: NM_174878
dbSNP: rs780412161
Type: single nucleotide variant
Location: chr3:150928133 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.74
Residue 168: a UniProt-annotated variant site (in ush3a)

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

Disease context

CLRN1-related disorder

Also linked: Usher syndrome type 3

Similar variants

CLRN1 p.Ile168fs Pathogenic/Likely pathogenic ★★ same residue
CLRN1 c.253+6T>C Pathogenic/Likely pathogenic ★★ same condition
CLRN1 c.254-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLRN1 c.254-649T>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

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-ile168phe (accessed [today's date]).

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