Is CLRN3 p.Leu78Ser (c.233T>C) pathogenic?

CLRN3 p.Leu78Ser (c.233T>C) is classified Uncertain significance in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.2058); Very rare (popmax 0.000169%, nfe).

How common is CLRN3 p.Leu78Ser (c.233T>C) in the general population?

CLRN3 p.Leu78Ser (c.233T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CLRN3 p.Leu78Ser (c.233T>C)?

AlphaMissense predicts likely benign (score 0.2058) — an in-silico prediction, not a clinical call.

CLRN3 p.Leu78Ser

c.233T>C · rs755477937 · VCV2210522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2058	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.19 · regional, not allelic
Overall
CADD	24.0	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 0.000169% European (non-Finnish) · 2/1,179,954 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,790 alleles · very rare

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.Leu78Ser
Coding: c.233T>C
MANE Select: NM_152311
dbSNP: rs755477937
Type: single nucleotide variant
Location: chr10:127883872 (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.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.Arg208Trp 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-leu78ser (accessed [today's date]).

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