Is CALCA p.Leu17Pro (c.50T>C) pathogenic?

CALCA p.Leu17Pro (c.50T>C) is classified Uncertain significance in CALCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: ambiguous (0.4461); Ultra-rare (popmax 0.0147%, afr).

How common is CALCA p.Leu17Pro (c.50T>C) in the general population?

CALCA p.Leu17Pro (c.50T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about CALCA p.Leu17Pro (c.50T>C)?

AlphaMissense predicts ambiguous (score 0.4461) — an in-silico prediction, not a clinical call.

CALCA p.Leu17Pro

c.50T>C · VCV3484335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4461 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4461	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -14.30	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 0.95
Regional constraint	o/e 0.98	unconstrained · MANE · 2,390 bp · p 0.75 · regional, not allelic
Overall
CADD	24.3	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 0.0147% African / African-American · 11/74,916 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000682% 11/1,614,014 alleles · ultra-rare

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: CALCA
Protein: p.Leu17Pro
Coding: c.50T>C
MANE Select: NM_001741
Type: single nucleotide variant
Location: chr11:14971143 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 64.12 · 6 PDB

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

Similar variants

CALCA p.Phe106= Benign ★★ same type
CALCA p.Ala118Val Uncertain significance ★ same type
CALCA p.Ala11Thr Uncertain significance ★ ⚠ same type
CALCA p.Ala31Ser Uncertain significance ★ ⚠ same type
CALCA p.Ala47Pro Uncertain significance ★ ⚠ same type
CALCA p.Ala47Val Uncertain significance ★ ⚠ same type
CALCA p.Arg123Cys Uncertain significance ★ same type
CALCA p.Arg84Gln 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/calca-p-leu17pro (accessed [today's date]).

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