Is CAPN3 p.Pro637Ser (c.1909C>T) pathogenic?

CAPN3 p.Pro637Ser (c.1909C>T) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). AlphaMissense: likely benign (0.064); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAPN3 p.Pro637Ser (c.1909C>T)?

CAPN3 p.Pro637Ser (c.1909C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN3 p.Pro637Ser (c.1909C>T) in the general population?

CAPN3 p.Pro637Ser (c.1909C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Pro637Ser (c.1909C>T)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

CAPN3 p.Pro637Ser

c.1909C>T · VCV3484832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -0.24, phastCons 0.13
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	8.716	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 0.00446% East Asian · 2/44,846 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000249% 4/1,608,394 alleles · very rare exomes 4/1,456,074 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,423
Admixed American	0.00167%	59,988
European (non-Finnish)	8.51e-05%	1,174,954

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: CAPN3
Protein: p.Pro637Ser
Coding: c.1909C>T
MANE Select: NM_000070
Type: single nucleotide variant
Location: chr15:42408319 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 637: the 'linker' region; the 'disordered' region

Full CAPN3 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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CAPN3 p.Ala385Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala750Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Arg386His Uncertain significance ★★ ⚠ same condition
CAPN3 p.Asn195Ser Uncertain significance ★★ ⚠ same condition
CAPN3 p.Asn415Ser 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/capn3-p-pro637ser (accessed [today's date]).

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