Is CLRN1 p.Cys20Ser (c.58T>A) pathogenic?

CLRN1 p.Cys20Ser (c.58T>A) is classified Uncertain significance in CLRN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1212); Very rare (popmax 0.00167%, amr).

How common is CLRN1 p.Cys20Ser (c.58T>A) in the general population?

CLRN1 p.Cys20Ser (c.58T>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLRN1 p.Cys20Ser (c.58T>A)?

AlphaMissense predicts likely benign (score 0.1212) — an in-silico prediction, not a clinical call.

CLRN1 p.Cys20Ser

c.58T>A · rs764138183 · VCV1046190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1212	likely benign
REVEL	0.469	indeterminate
SaProt	LLR -4.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	21.2	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 0.00167% Admixed American · 1/60,034 alleles

Overall 6.84e-05% 1/1,461,894 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.Cys20Ser
Coding: c.58T>A
MANE Select: NM_174878
dbSNP: rs764138183
Type: single nucleotide variant
Location: chr3:150972651 (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

Similar variants

CLRN1 p.Cys20Ter Pathogenic ★ same residue
CLRN1 p.Cys20Arg Uncertain significance ★ ⚠ same residue
CLRN1 p.Cys20= Likely benign ★ same residue
CLRN1 c.253+1G>A Likely pathogenic ★★ same type
CLRN1 c.253+6T>C Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.254-2A>G Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.254-649T>G Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.433+1G>A Pathogenic/Likely pathogenic ★★ same type

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-cys20ser (accessed [today's date]).

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