Is CLRN1 p.Ala123Asp (c.368C>A) pathogenic?

CLRN1 p.Ala123Asp (c.368C>A) is classified Pathogenic/Likely pathogenic in CLRN1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.8826); Ultra-rare (popmax 0.052%, afr); Associated with CLRN1-related disorder.

What condition is associated with CLRN1 p.Ala123Asp (c.368C>A)?

CLRN1 p.Ala123Asp (c.368C>A) is associated with CLRN1-related disorder, Usher syndrome type 3A, retinitis pigmentosa 61 (ClinVar).

How common is CLRN1 p.Ala123Asp (c.368C>A) in the general population?

CLRN1 p.Ala123Asp (c.368C>A) is ultra-rare (popmax 0.052%, afr) (gnomAD).

What do computational predictors say about CLRN1 p.Ala123Asp (c.368C>A)?

AlphaMissense predicts likely pathogenic (score 0.8826) — an in-silico prediction, not a clinical call.

CLRN1 p.Ala123Asp

c.368C>A · rs374963432 · VCV48146

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8826 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.052%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLRN1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8826	likely pathogenic ✓ concordant with ClinVar · top 4% in CLRN1
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	27.8	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 0.052% African / African-American · 39/75,044 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0345%

Overall 0.00254% 41/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.052%	1,924
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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.Ala123Asp
Coding: c.368C>A
MANE Select: NM_174878
dbSNP: rs374963432
Type: single nucleotide variant
Location: chr3:150941647 (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

CLRN1-related disorder

Also linked: Usher syndrome type 3A retinitis pigmentosa 61 Usher syndrome type 3 Usher syndrome

Similar variants

CLRN1 c.253+1G>A Likely pathogenic ★★ same condition
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.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Asn202Lys 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-ala123asp (accessed [today's date]).

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