Is CALCA p.Pro36Thr (c.106C>A) pathogenic?

CALCA p.Pro36Thr (c.106C>A) is classified Uncertain significance in CALCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.0798); Ultra-rare (popmax 0.0987%, mid).

How common is CALCA p.Pro36Thr (c.106C>A) in the general population?

CALCA p.Pro36Thr (c.106C>A) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

What do computational predictors say about CALCA p.Pro36Thr (c.106C>A)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

CALCA p.Pro36Thr

c.106C>A · VCV3484334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.33	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 -0.86	GERP 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,390 bp · p 0.75 · regional, not allelic
Overall
CADD	13.73	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 0.0987% Middle Eastern · 6/6,082 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00285% 46/1,614,112 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,014
South Asian	0.00329%	30,361
European (non-Finnish)	0.00297%	33,716
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro36Thr
Coding: c.106C>A
MANE Select: NM_001741
Type: single nucleotide variant
Location: chr11:14970056 (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-pro36thr (accessed [today's date]).

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