Is CAPN6 p.Cys506Phe (c.1517G>T) pathogenic?

CAPN6 p.Cys506Phe (c.1517G>T) is classified Uncertain significance in CAPN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.134); Very rare (popmax 0.00875%, amr).

How common is CAPN6 p.Cys506Phe (c.1517G>T) in the general population?

CAPN6 p.Cys506Phe (c.1517G>T) is very rare (popmax 0.00875%, amr) (gnomAD).

What do computational predictors say about CAPN6 p.Cys506Phe (c.1517G>T)?

AlphaMissense predicts likely benign (score 0.134) — an in-silico prediction, not a clinical call.

CAPN6 p.Cys506Phe

c.1517G>T · VCV4218908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00875%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.134	likely benign
REVEL	0.718	pathogenic-leaning
SaProt	LLR -6.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 17 kb · p 0.098 · regional, not allelic
Overall
CADD	25.4	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 0.00875% Admixed American · 4/45,740 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000579% 7/1,209,093 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00875%	11,435
Remaining individualsnot grpmax-eligible	0.00631%	15,859

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.Cys506Phe
Coding: c.1517G>T
MANE Select: NM_014289
Type: single nucleotide variant
Location: chrX:111247960 (GRCh38)
Structure: AlphaFold pLDDT 91.57
Residue 506: the c2 domain

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-cys506phe (accessed [today's date]).

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