Is C2 p.Leu13fs (c.37del) pathogenic?

C2 p.Leu13fs (c.37del) is classified Pathogenic in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-13). Very rare (popmax 0.000169%, nfe).

How common is C2 p.Leu13fs (c.37del) in the general population?

C2 p.Leu13fs (c.37del) is very rare (popmax 0.000169%, nfe) (gnomAD).

C2 p.Leu13fs

c.37del · rs1394227134 · VCV1452098

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.9	GERP -3.2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,994 alleles

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

Overall 0.000137% 2/1,461,574 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: C2
Protein: p.Leu13fs
Coding: c.37del
MANE Select: NM_000063
dbSNP: rs1394227134
Type: Deletion
Location: chr6:31927788 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2 p.Leu13Pro Uncertain significance ★ ⚠ same residue
C2 c.841_849+19del Pathogenic/Likely pathogenic ★★ same type
C2 c.1455+17del Benign/Likely benign ★★ same type
C2 c.1567+22_1567+43del Benign/Likely benign ★★ same type
C2 c.1811-16del Benign/Likely benign ★★ same type
C2 p.Ala495fs Likely pathogenic ★ same type
C2 p.Gly597fs Pathogenic ★ same type
C2 p.Met280fs Likely pathogenic ★ 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/c2-p-leu13fs (accessed [today's date]).

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