Is CALCA p.Ser30Cys (c.89C>G) pathogenic?

CALCA p.Ser30Cys (c.89C>G) is classified Uncertain significance in CALCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1664); Very rare (popmax 0.00237%, nfe).

How common is CALCA p.Ser30Cys (c.89C>G) in the general population?

CALCA p.Ser30Cys (c.89C>G) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about CALCA p.Ser30Cys (c.89C>G)?

AlphaMissense predicts likely benign (score 0.1664) — an in-silico prediction, not a clinical call.

CALCA p.Ser30Cys

c.89C>G · VCV3994758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1664	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -11.00	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP 1.3
Regional constraint	o/e 0.98	unconstrained · MANE · 2,390 bp · p 0.75 · regional, not allelic
Overall
CADD	18.47	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 0.00237% European (non-Finnish) · 28/1,180,032 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00192% 31/1,614,084 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.00237%	42,144
African / African-American	0.00133%	74,944

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser30Cys
Coding: c.89C>G
MANE Select: NM_001741
Type: single nucleotide variant
Location: chr11:14970073 (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-ser30cys (accessed [today's date]).

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