Is CALCA p.Pro137Thr (c.409C>A) pathogenic?

CALCA p.Pro137Thr (c.409C>A) is classified Uncertain significance in CALCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-28). AlphaMissense: likely benign (0.0837); Absent from gnomAD v4.1.

How common is CALCA p.Pro137Thr (c.409C>A) in the general population?

CALCA p.Pro137Thr (c.409C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALCA p.Pro137Thr (c.409C>A)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

CALCA p.Pro137Thr

c.409C>A · VCV3484337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.30	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 -0.83	GERP -1.1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,390 bp · p 0.75 · regional, not allelic
Overall
CADD	0.18	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CALCA
Protein: p.Pro137Thr
Coding: c.409C>A
MANE Select: NM_001741
Type: single nucleotide variant
Location: chr11:14968816 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 64.12 · 6 PDB
Residue 137: the 'disordered' region

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

Similar variants

CALCA p.Pro137Ser Uncertain significance ★ ⚠ same residue
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

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-pro137thr (accessed [today's date]).

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