Is CLRN2 p.Ser209Thr (c.626G>C) pathogenic?

CLRN2 p.Ser209Thr (c.626G>C) is classified Uncertain significance in CLRN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.1429); Ultra-rare (popmax 0.04%, amr).

How common is CLRN2 p.Ser209Thr (c.626G>C) in the general population?

CLRN2 p.Ser209Thr (c.626G>C) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about CLRN2 p.Ser209Thr (c.626G>C)?

AlphaMissense predicts likely benign (score 0.1429) — an in-silico prediction, not a clinical call.

CLRN2 p.Ser209Thr

c.626G>C · VCV3493902

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1429	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -9.28	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 12	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.51 · regional, not allelic
Overall
CADD	24.6	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 0.04% Admixed American · 24/60,006 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00285% 46/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,500
South Asian	0.0198%	5,060
African / African-American	0.00267%	37,464
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	8.48e-05%	1,179,892

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.Ser209Thr
Coding: c.626G>C
MANE Select: NM_001079827
Type: single nucleotide variant
Location: chr4:17527009 (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-ser209thr (accessed [today's date]).

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