Is CAPN1 p.Phe610Cys (c.1829T>G) pathogenic?

CAPN1 p.Phe610Cys (c.1829T>G) is classified Uncertain significance in CAPN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.9951); Ultra-rare (popmax 0.0968%, nfe).

How common is CAPN1 p.Phe610Cys (c.1829T>G) in the general population?

CAPN1 p.Phe610Cys (c.1829T>G) is ultra-rare (popmax 0.0968%, nfe) (gnomAD).

What do computational predictors say about CAPN1 p.Phe610Cys (c.1829T>G)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

CAPN1 p.Phe610Cys

c.1829T>G · rs200876514 · VCV2071485

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0968%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 10% in CAPN1
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0968% European (non-Finnish) · 1,142/1,179,852 alleles

Filtering AF 0.0921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0902%

Overall 0.0741% 1,195/1,613,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0968%	1,033
Remaining individualsnot grpmax-eligible	0.0528%	1,893
Admixed American	0.0167%	5,999
African / African-American	0.012%	8,322
Finnishnot grpmax-eligible	0.00157%	63,824

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.Phe610Cys
Coding: c.1829T>G
MANE Select: NM_005186
dbSNP: rs200876514
Type: single nucleotide variant
Location: chr11:65209883 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 610: the ef-hand 2 domain; the 'domain iv' region

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.338-1G>A Pathogenic ★★ same type
CAPN1 c.759+1G>A Pathogenic ★★ same type
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.929+2T>A Likely pathogenic ★★ same type
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same type
CAPN1 p.Arg385Ter Pathogenic/Likely pathogenic ★★ 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/capn1-p-phe610cys (accessed [today's date]).

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