Is CCM2 p.Leu59fs (c.174dup) pathogenic?

CCM2 p.Leu59fs (c.174dup) is classified Pathogenic in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-23). Absent from gnomAD.

How common is CCM2 p.Leu59fs (c.174dup) in the general population?

CCM2 p.Leu59fs (c.174dup) is absent from gnomAD (gnomAD).

CCM2 p.Leu59fs

c.174dup · rs1554365577 · VCV524145

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 2 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CCM2
Protein: p.Leu59fs
Coding: c.174dup
MANE Select: NM_031443
dbSNP: rs1554365577
Type: Duplication
Location: chr7:45038395 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 59: the pid domain; a turn

Full CCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCM2 p.Arg412fs Pathogenic/Likely pathogenic ★★ same type
CCM2 p.Glu191fs Pathogenic ★ same type
CCM2 p.Glu359delinsProTer Pathogenic ★ same type
CCM2 p.Glu66fs Pathogenic ★ same type
CCM2 p.His104fs Pathogenic ★ same type
CCM2 p.Leu58fs Pathogenic ★ same type
CCM2 p.Pro77fs Pathogenic ★ same type
CCM2 p.Trp124fs 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/ccm2-p-leu59fs (accessed [today's date]).

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