Is CAPN1 p.Leu68= (c.204G>C) pathogenic?

CAPN1 p.Leu68= (c.204G>C) is classified Benign in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). Low-frequency (popmax 1.14%, sas).

How common is CAPN1 p.Leu68= (c.204G>C) in the general population?

CAPN1 p.Leu68= (c.204G>C) is low-frequency (popmax 1.14%, sas) (gnomAD).

CAPN1 p.Leu68=

c.204G>C · rs17881440 · VCV781962

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -4.8, phastCons 1
Overall
CADD	7.714	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.14% South Asian · 1,028/90,338 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.135% 2,179/1,610,132 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.23%	81
South Asiangrpmax	1.14%	88
Middle Eastern	0.33%	303
Finnishnot grpmax-eligible	0.324%	308
Remaining individualsnot grpmax-eligible	0.223%	449
European (non-Finnish)	0.0345%	2,895
Admixed American	0.0135%	7,412
African / African-American	0.0107%	9,367

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CAPN1
Protein: p.Leu68=
Coding: c.204G>C
MANE Select: NM_005186
dbSNP: rs17881440
Type: single nucleotide variant
Location: chr11:65182905 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 68: the calpain catalytic domain; an α-helix

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.338-1G>A Pathogenic ★★ same type
CAPN1 c.759+1G>A Pathogenic ★★ same type
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.929+2T>A Likely pathogenic ★★ same type
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same type
CAPN1 p.Arg385Ter Pathogenic/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/capn1-p-leu68 (accessed [today's date]).

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