Is CLRN2 p.Tyr63Cys (c.188A>G) pathogenic?

CLRN2 p.Tyr63Cys (c.188A>G) is classified Uncertain significance in CLRN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.4325); Very rare (popmax 0.0011%, sas).

How common is CLRN2 p.Tyr63Cys (c.188A>G) in the general population?

CLRN2 p.Tyr63Cys (c.188A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLRN2 p.Tyr63Cys (c.188A>G)?

AlphaMissense predicts ambiguous (score 0.4325) — an in-silico prediction, not a clinical call.

CLRN2 p.Tyr63Cys

c.188A>G · VCV4003836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4325	ambiguous
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -12.20	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.51 · regional, not allelic
Overall
CADD	24.1	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000753% 11/1,461,692 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000848%	117,985

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.Tyr63Cys
Coding: c.188A>G
MANE Select: NM_001079827
Type: single nucleotide variant
Location: chr4:17515454 (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

Similar variants

CLRN2 p.Arg79Leu Uncertain significance ★★ ⚠ same type
CLRN2 p.Cys69Tyr 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-tyr63cys (accessed [today's date]).

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