Is CAPN1 p.Asp667Asn (c.1999G>A) pathogenic?

CAPN1 p.Asp667Asn (c.1999G>A) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.1194); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Asp667Asn (c.1999G>A)?

CAPN1 p.Asp667Asn (c.1999G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Asp667Asn (c.1999G>A) in the general population?

CAPN1 p.Asp667Asn (c.1999G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CAPN1 p.Asp667Asn (c.1999G>A)?

AlphaMissense predicts likely benign (score 0.1194) — an in-silico prediction, not a clinical call.

CAPN1 p.Asp667Asn

c.1999G>A · rs561601246 · VCV2387458

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1194 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1194	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP -1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00229% 37/1,613,264 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.00439%	22,756
Remaining individualsnot grpmax-eligible	0.0032%	31,226
European (non-Finnish)	0.00237%	42,134
Admixed American	0.00167%	59,958

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.Asp667Asn
Coding: c.1999G>A
MANE Select: NM_005186
dbSNP: rs561601246
Type: single nucleotide variant
Location: chr11:65210392 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 667: the 'domain iv' region

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

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CAPN1 p.Arg347Cys Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg48Gln Uncertain significance ★★ ⚠ same condition
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CAPN1 p.Arg599His 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-asp667asn (accessed [today's date]).

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