Is CLRN2 p.Ser197Leu (c.590C>T) pathogenic?

CLRN2 p.Ser197Leu (c.590C>T) is classified Likely benign in CLRN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-01). AlphaMissense: likely benign (0.0762); Ultra-rare (popmax 0.0198%, sas).

How common is CLRN2 p.Ser197Leu (c.590C>T) in the general population?

CLRN2 p.Ser197Leu (c.590C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about CLRN2 p.Ser197Leu (c.590C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

CLRN2 p.Ser197Leu

c.590C>T · rs762164219 · VCV2654687

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -5.72	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 3.3	phastCons 0.85
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.51 · regional, not allelic
Overall
CADD	10.08	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 0.0198% South Asian · 18/91,082 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00149% 24/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00223%	44,878
African / African-American	0.00133%	75,042

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.Ser197Leu
Coding: c.590C>T
MANE Select: NM_001079827
dbSNP: rs762164219
Type: single nucleotide variant
Location: chr4:17526973 (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-ser197leu (accessed [today's date]).

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