Is CLRN3 p.Arg208Trp (c.622C>T) pathogenic?

CLRN3 p.Arg208Trp (c.622C>T) is classified Uncertain significance in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1068); Ultra-rare (popmax 0.0165%, mid).

How common is CLRN3 p.Arg208Trp (c.622C>T) in the general population?

CLRN3 p.Arg208Trp (c.622C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLRN3 p.Arg208Trp (c.622C>T)?

AlphaMissense predicts likely benign (score 0.1068) — an in-silico prediction, not a clinical call.

CLRN3 p.Arg208Trp

c.622C>T · VCV4230166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1068	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.54	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 1.9	GERP -1.2, phastCons 0.18
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.19 · regional, not allelic
Overall
CADD	23.4	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00328% 53/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.0133%	7,502
South Asian	0.00549%	18,218
East Asian	0.00446%	22,445
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	0.00288%	34,705
African / African-American	0.00133%	75,048

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: CLRN3
Protein: p.Arg208Trp
Coding: c.622C>T
MANE Select: NM_152311
Type: single nucleotide variant
Location: chr10:127878208 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.68

Full CLRN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLRN3 p.Arg208Gln Likely benign ★ same residue
CLRN3 p.Ala149Glu Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Ser Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Thr Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Val Uncertain significance ★ ⚠ same type
CLRN3 p.Asn46His Uncertain significance ★ ⚠ same type
CLRN3 p.Gln207Arg Uncertain significance ★ ⚠ same type
CLRN3 p.Gln31Pro 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/clrn3-p-arg208trp (accessed [today's date]).

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