Is CGNL1 p.Leu366Pro (c.1097T>C) pathogenic?

CGNL1 p.Leu366Pro (c.1097T>C) is classified Uncertain significance in CGNL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.005%, nfe).

How common is CGNL1 p.Leu366Pro (c.1097T>C) in the general population?

CGNL1 p.Leu366Pro (c.1097T>C) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about CGNL1 p.Leu366Pro (c.1097T>C)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

CGNL1 p.Leu366Pro

c.1097T>C · rs138609543 · VCV2491742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.66	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 1.4	GERP -0.2, phastCons 0.006
Regional constraint	o/e 1.18	unconstrained · MANE · 109 kb · p 1.7e-12 · regional, not allelic
Overall
CADD	13.24	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 0.005% European (non-Finnish) · 59/1,180,042 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00384% 62/1,614,072 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,916

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: CGNL1
Protein: p.Leu366Pro
Coding: c.1097T>C
MANE Select: NM_032866
dbSNP: rs138609543
Type: single nucleotide variant
Location: chr15:57439096 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.25
Residue 366: the 'head' region; the 'disordered' region

Full CGNL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CGNL1 p.Asn937= Benign ★★ same type
CGNL1 p.Ile1155= Benign ★★ same type
CGNL1 p.Thr568Ala Likely benign ★★ same type
CGNL1 p.Ala109Thr Uncertain significance ★ ⚠ same type
CGNL1 p.Ala1156Thr Uncertain significance ★ ⚠ same type
CGNL1 p.Ala1156Val Uncertain significance ★ ⚠ same type
CGNL1 p.Ala209Thr Uncertain significance ★ ⚠ same type
CGNL1 p.Ala306Asp 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/cgnl1-p-leu366pro (accessed [today's date]).

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