Is CAPN6 p.Arg408Cys (c.1222C>T) pathogenic?

CAPN6 p.Arg408Cys (c.1222C>T) is classified Uncertain significance in CAPN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.2968); Ultra-rare (popmax 0.0106%, sas).

How common is CAPN6 p.Arg408Cys (c.1222C>T) in the general population?

CAPN6 p.Arg408Cys (c.1222C>T) is ultra-rare (popmax 0.0106%, sas) (gnomAD).

What do computational predictors say about CAPN6 p.Arg408Cys (c.1222C>T)?

AlphaMissense predicts likely benign (score 0.2968) — an in-silico prediction, not a clinical call.

CAPN6 p.Arg408Cys

c.1222C>T · VCV3484842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2968	likely benign
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -13.35	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 5.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 17 kb · p 0.098 · regional, not allelic
Overall
CADD	26.2	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 0.0106% South Asian · 6/56,718 alleles

Filtering AF 0.00459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00108% 13/1,208,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0106%	9,453
African / African-American	0.00526%	19,018
Remaining individualsnot grpmax-eligible	0.00421%	23,780
European (non-Finnish)	0.000224%	447,183

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: CAPN6
Protein: p.Arg408Cys
Coding: c.1222C>T
MANE Select: NM_014289
Type: single nucleotide variant
Location: chrX:111248994 (GRCh38)
Structure: AlphaFold pLDDT 91.57
Residue 408: the 'domain iii' region

Full CAPN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN6 c.1158+128A>T Benign ★★ same type
CAPN6 c.1743+105G>A Benign ★★ same type
CAPN6 c.297+86C>T Benign ★★ same type
CAPN6 c.699+25C>T Benign ★★ same type
CAPN6 c.700-159T>C Benign ★★ same type
CAPN6 p.Tyr117= Benign ★★ same type
CAPN6 p.Val277Leu Benign ★★ same type
CAPN6 p.Arg260Cys 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/capn6-p-arg408cys (accessed [today's date]).

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