Is CLRN1 p.Pro134Ser (c.400C>T) pathogenic?

CLRN1 p.Pro134Ser (c.400C>T) is classified Uncertain significance in CLRN1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-03-08). AlphaMissense: likely benign (0.238); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLRN1 p.Pro134Ser (c.400C>T)?

CLRN1 p.Pro134Ser (c.400C>T) is associated with Inborn genetic diseases, Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Pro134Ser (c.400C>T) in the general population?

CLRN1 p.Pro134Ser (c.400C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CLRN1 p.Pro134Ser (c.400C>T)?

AlphaMissense predicts likely benign (score 0.238) — an in-silico prediction, not a clinical call.

CLRN1 p.Pro134Ser

c.400C>T · rs368175674 · VCV938719

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.238	likely benign
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -9.37	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	25.7	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 0.0227% African / African-American · 17/74,904 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00149% 24/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.000424%	235,988

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.Pro134Ser
Coding: c.400C>T
MANE Select: NM_174878
dbSNP: rs368175674
Type: single nucleotide variant
Location: chr3:150941615 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 3

Similar variants

CLRN1 p.Pro134Leu Uncertain significance ★★ ⚠ same residue
CLRN1 p.Pro134Ala Uncertain significance ★ ⚠ same residue
CLRN1 p.Pro134= Likely benign ★ same residue
CLRN1 p.Pro134Arg 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

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-pro134ser (accessed [today's date]).

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