Is CALCA p.Val16Ile (c.46G>A) pathogenic?

CALCA p.Val16Ile (c.46G>A) is classified Uncertain significance in CALCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1121); Very rare (popmax 0.00167%, amr).

How common is CALCA p.Val16Ile (c.46G>A) in the general population?

CALCA p.Val16Ile (c.46G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CALCA p.Val16Ile (c.46G>A)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

CALCA p.Val16Ile

c.46G>A · VCV4218238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.81	GERP 0.23
Regional constraint	o/e 0.98	unconstrained · MANE · 2,390 bp · p 0.75 · regional, not allelic
Overall
CADD	17.46	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 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000124% 2/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00134%	74,864

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.Val16Ile
Coding: c.46G>A
MANE Select: NM_001741
Type: single nucleotide variant
Location: chr11:14971147 (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-val16ile (accessed [today's date]).

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