Is CAPN1 p.Arg347His (c.1040G>A) pathogenic?

CAPN1 p.Arg347His (c.1040G>A) is classified Uncertain significance in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). AlphaMissense: likely pathogenic (0.7911); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Arg347His (c.1040G>A)?

CAPN1 p.Arg347His (c.1040G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Arg347His (c.1040G>A) in the general population?

CAPN1 p.Arg347His (c.1040G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CAPN1 p.Arg347His (c.1040G>A)?

AlphaMissense predicts likely pathogenic (score 0.7911) — an in-silico prediction, not a clinical call.

CAPN1 p.Arg347His

c.1040G>A · rs372172705 · VCV2187805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7911	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -9.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	27.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00626% 101/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00746%	13,408
African / African-American	0.00533%	18,754
South Asian	0.0022%	45,539
Admixed American	0.00167%	60,008

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.Arg347His
Coding: c.1040G>A
MANE Select: NM_005186
dbSNP: rs372172705
Type: single nucleotide variant
Location: chr11:65188621 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 347: the calpain catalytic domain; a β-strand

Full CAPN1 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

CAPN1 p.Arg347Cys Uncertain significance ★★ ⚠ same residue
CAPN1 p.Arg104His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Trp Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg48Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg581Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg599His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg681Gln 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/capn1-p-arg347his (accessed [today's date]).

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