Is CALU p.Val124Ile (c.370G>A) pathogenic?

CALU p.Val124Ile (c.370G>A) is classified Uncertain significance in CALU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0797); Very rare (popmax 0.00223%, eas).

How common is CALU p.Val124Ile (c.370G>A) in the general population?

CALU p.Val124Ile (c.370G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CALU p.Val124Ile (c.370G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

CALU p.Val124Ile

c.370G>A · VCV3994860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -3.71	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 6.8	phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 21 kb · p 3e-08 · regional, not allelic
Overall
CADD	19.64	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000593%	168,574

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.Val124Ile
Coding: c.370G>A
MANE Select: NM_001219
Type: single nucleotide variant
Location: chr7:128754410 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 79.82
Residue 124: the ef-hand 2 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-val124ile (accessed [today's date]).

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