Is CLRN1 p.Val177Ile (c.529G>A) pathogenic?

CLRN1 p.Val177Ile (c.529G>A) is classified Uncertain significance in CLRN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0704); Very rare (popmax 0.00668%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLRN1 p.Val177Ile (c.529G>A)?

CLRN1 p.Val177Ile (c.529G>A) is associated with Inborn genetic diseases, Usher syndrome type 3A (ClinVar).

How common is CLRN1 p.Val177Ile (c.529G>A) in the general population?

CLRN1 p.Val177Ile (c.529G>A) is very rare (popmax 0.00668%, amr) (gnomAD).

What do computational predictors say about CLRN1 p.Val177Ile (c.529G>A)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

CLRN1 p.Val177Ile

c.529G>A · rs753739519 · VCV840237

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -5.29	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 0.4	GERP 0.95, phastCons 0.032
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% Admixed American · 4/59,890 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000342% 5/1,461,346 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,973
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Val177Ile
Coding: c.529G>A
MANE Select: NM_174878
dbSNP: rs753739519
Type: single nucleotide variant
Location: chr3:150928106 (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 3A

Similar variants

CLRN1 c.253+1G>A Likely pathogenic ★★ same condition
CLRN1 c.253+6T>C Pathogenic/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
CLRN1 p.Asn48Lys Pathogenic ★★ same condition
CLRN1 p.Gln181Ter Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Gln5Ter 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-val177ile (accessed [today's date]).

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