Is CALU p.Val291Ile (c.871G>A) pathogenic?

CALU p.Val291Ile (c.871G>A) is classified Uncertain significance in CALU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0756); Ultra-rare (popmax 0.0467%, amr).

How common is CALU p.Val291Ile (c.871G>A) in the general population?

CALU p.Val291Ile (c.871G>A) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about CALU p.Val291Ile (c.871G>A)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

CALU p.Val291Ile

c.871G>A · VCV3826980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -6.46	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 12	phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 21 kb · p 3e-08 · regional, not allelic
Overall
CADD	23.0	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 0.0467% Admixed American · 28/59,956 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.0036% 58/1,611,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,141
East Asian	0.00669%	14,955
Remaining individualsnot grpmax-eligible	0.00321%	31,201
African / African-American	0.00267%	37,417
South Asian	0.0022%	45,514
European (non-Finnish)	0.00178%	56,108

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: CALU
Protein: p.Val291Ile
Coding: c.871G>A
MANE Select: NM_001219
Type: single nucleotide variant
Location: chr7:128769090 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 79.82
Residue 291: the ef-hand 6 domain

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

Similar variants

OPN1SW p.Ala309Pro Uncertain significance ★★ ⚠ same type
OPN1SW p.Ser335Phe Uncertain significance ★★ ⚠ same type
OPN1SW p.Ser324= Likely benign ★★ same type
OPN1SW p.Ser338= Benign/Likely benign ★★ same type
CALU p.Arg234Ter Likely pathogenic ★ same type
CALU c.-11-208C>G Uncertain significance ★ same type
CALU c.-3A>G Uncertain significance ★ same type
CALU c.*3456C>A 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/calu-p-val291ile (accessed [today's date]).

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