Is CAPSL p.Leu44Pro (c.131T>C) pathogenic?

CAPSL p.Leu44Pro (c.131T>C) is classified Uncertain significance in CAPSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9715); Very rare (popmax 0.0011%, sas).

How common is CAPSL p.Leu44Pro (c.131T>C) in the general population?

CAPSL p.Leu44Pro (c.131T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CAPSL p.Leu44Pro (c.131T>C)?

AlphaMissense predicts likely pathogenic (score 0.9715) — an in-silico prediction, not a clinical call.

CAPSL p.Leu44Pro

c.131T>C · VCV3995336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9715 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9715	likely pathogenic · top 7% in CAPSL
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -17.61	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 17 kb · p 0.065 · regional, not allelic
Overall
CADD	30.0	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 0.0011% South Asian · 1/91,028 alleles

Overall 0.000137% 2/1,461,506 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,028
European (non-Finnish)	8.48e-05%	1,179,884

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: CAPSL
Protein: p.Leu44Pro
Coding: c.131T>C
MANE Select: NM_001042625
Type: single nucleotide variant
Location: chr5:35920990 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 44: the ef-hand 1 domain

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

Similar variants

CAPSL p.Phe61Val Uncertain significance ★★ ⚠ same type
CAPSL p.Met201Val Benign ★★ ⚠ same type
CAPSL p.Ala2Ser Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Cys Uncertain significance ★ ⚠ same type
CAPSL p.Arg137His Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Leu Uncertain significance ★ ⚠ same type
CAPSL p.Arg160Thr Uncertain significance ★ ⚠ same type
CAPSL p.Asp135Glu Uncertain significance ★ ⚠ 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/capsl-p-leu44pro (accessed [today's date]).

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