Is CLRN3 p.Pro126Leu (c.377C>T) pathogenic?

CLRN3 p.Pro126Leu (c.377C>T) is classified Uncertain significance in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely benign (0.3285); Rare (popmax 0.128%, sas).

How common is CLRN3 p.Pro126Leu (c.377C>T) in the general population?

CLRN3 p.Pro126Leu (c.377C>T) is rare (popmax 0.128%, sas) (gnomAD).

What do computational predictors say about CLRN3 p.Pro126Leu (c.377C>T)?

AlphaMissense predicts likely benign (score 0.3285) — an in-silico prediction, not a clinical call.

CLRN3 p.Pro126Leu

c.377C>T · VCV3267867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3285 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.128%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3285	likely benign
REVEL	0.772	pathogenic-leaning
SaProt	LLR -6.57	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.19 · regional, not allelic
Overall
CADD	28.1	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 0.128% South Asian · 117/91,058 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.022% 355/1,613,800 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.128%	778
Remaining individualsnot grpmax-eligible	0.0256%	3,906
European (non-Finnish)	0.0176%	5,672
Admixed American	0.015%	6,669
East Asian	0.00446%	22,436
African / African-American	0.004%	24,988

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.Pro126Leu
Coding: c.377C>T
MANE Select: NM_152311
Type: single nucleotide variant
Location: chr10:127883728 (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-pro126leu (accessed [today's date]).

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