Is CAPN5 p.Arg408Trp (c.1222C>T) pathogenic?

CAPN5 p.Arg408Trp (c.1222C>T) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.1245); Ultra-rare (popmax 0.0706%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Arg408Trp (c.1222C>T)?

CAPN5 p.Arg408Trp (c.1222C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Arg408Trp (c.1222C>T) in the general population?

CAPN5 p.Arg408Trp (c.1222C>T) is ultra-rare (popmax 0.0706%, afr) (gnomAD).

What do computational predictors say about CAPN5 p.Arg408Trp (c.1222C>T)?

AlphaMissense predicts likely benign (score 0.1245) — an in-silico prediction, not a clinical call.

CAPN5 p.Arg408Trp

c.1222C>T · rs374843302 · VCV1118043

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1245 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0706%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1245	likely benign
REVEL	0.665	pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	29.4	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 0.0706% African / African-American · 53/75,080 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00762% 123/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0811%	1,233
African / African-Americangrpmax	0.0706%	1,417
Admixed American	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00271%	36,874
South Asian	0.0011%	91,026

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: CAPN5
Protein: p.Arg408Trp
Coding: c.1222C>T
MANE Select: NM_004055
dbSNP: rs374843302
Type: single nucleotide variant
Location: chr11:77119084 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 408: the 'domain iii' region

Full CAPN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN5 p.Arg408Gln Likely benign ★★ same residue
CAPN5 p.Arg408Leu Uncertain significance ★ ⚠ same residue
CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala34Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala357Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala362Gly Uncertain significance ★★ ⚠ same condition

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/capn5-p-arg408trp (accessed [today's date]).

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