Is CLRN2 p.Cys69Tyr (c.206G>A) pathogenic?

CLRN2 p.Cys69Tyr (c.206G>A) is classified Uncertain significance in CLRN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-19). AlphaMissense: likely benign (0.0765); Rare (popmax 0.106%, nfe); Associated with CLRN2-related disorder.

What condition is associated with CLRN2 p.Cys69Tyr (c.206G>A)?

CLRN2 p.Cys69Tyr (c.206G>A) is associated with CLRN2-related disorder (ClinVar).

How common is CLRN2 p.Cys69Tyr (c.206G>A) in the general population?

CLRN2 p.Cys69Tyr (c.206G>A) is rare (popmax 0.106%, nfe) (gnomAD).

What do computational predictors say about CLRN2 p.Cys69Tyr (c.206G>A)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CLRN2 p.Cys69Tyr

c.206G>A · rs200819557 · VCV2362909

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CLRN2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -1.97	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 6.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.51 · regional, not allelic
Overall
CADD	21.4	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 0.106% European (non-Finnish) · 1,249/1,179,894 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.099%

Overall 0.0844% 1,362/1,613,994 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.106%	945
Admixed American	0.0883%	1,132
Remaining individualsnot grpmax-eligible	0.064%	1,562
African / African-American	0.0253%	3,949
Finnishnot grpmax-eligible	0.00156%	64,020

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: CLRN2
Protein: p.Cys69Tyr
Coding: c.206G>A
MANE Select: NM_001079827
dbSNP: rs200819557
Type: single nucleotide variant
Location: chr4:17515472 (GRCh38)
Gene constraint: LOEUF 1.19 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15

Full CLRN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLRN2-related disorder

Similar variants

CLRN2 p.His199Leu Likely benign same condition
CLRN2 p.Arg79Leu Uncertain significance ★★ ⚠ same type
CLRN2 p.Leu113Val Benign ★★ same type
CLRN2 p.Ala144Thr Uncertain significance ★ ⚠ same type
CLRN2 p.Ala158Val Uncertain significance ★ ⚠ same type
CLRN2 p.Ala207Val Uncertain significance ★ ⚠ same type
CLRN2 p.Ala27Thr Uncertain significance ★ ⚠ same type
CLRN2 p.Ala49Thr Uncertain significance ★ ⚠ 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/clrn2-p-cys69tyr (accessed [today's date]).

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