Is CAPN1 p.Pro533Ser (c.1597C>T) pathogenic?

CAPN1 p.Pro533Ser (c.1597C>T) is classified Likely benign in CAPN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.1754); Rare (popmax 0.33%, mid).

How common is CAPN1 p.Pro533Ser (c.1597C>T) in the general population?

CAPN1 p.Pro533Ser (c.1597C>T) is rare (popmax 0.33%, mid) (gnomAD).

What do computational predictors say about CAPN1 p.Pro533Ser (c.1597C>T)?

AlphaMissense predicts likely benign (score 0.1754) — an in-silico prediction, not a clinical call.

CAPN1 p.Pro533Ser

c.1597C>T · rs150244086 · VCV735663

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1754 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1754	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -9.90	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 7.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	22.4	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 0.33% Middle Eastern · 20/6,056 alleles

Filtering AF 0.229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.226%

Overall 0.193% 3,119/1,612,332 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.33%	303
European (non-Finnish)	0.236%	423
Ashkenazi Jewishnot grpmax-eligible	0.189%	528
Remaining individualsnot grpmax-eligible	0.173%	578
Admixed American	0.104%	965
Finnishnot grpmax-eligible	0.0565%	1,770
African / African-American	0.0333%	3,000
South Asian	0.0265%	3,778

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.Pro533Ser
Coding: c.1597C>T
MANE Select: NM_005186
dbSNP: rs150244086
Type: single nucleotide variant
Location: chr11:65206811 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 533: the 'linker' region

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

Similar variants

CAPN1 p.Pro533= Likely benign ★ same residue
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

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-pro533ser (accessed [today's date]).

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