Is CALML5 p.Arg133Trp (c.397C>T) pathogenic?

CALML5 p.Arg133Trp (c.397C>T) is classified Uncertain significance in CALML5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely benign (0.2381); Very rare (popmax 0.00226%, eas).

How common is CALML5 p.Arg133Trp (c.397C>T) in the general population?

CALML5 p.Arg133Trp (c.397C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about CALML5 p.Arg133Trp (c.397C>T)?

AlphaMissense predicts likely benign (score 0.2381) — an in-silico prediction, not a clinical call.

CALML5 p.Arg133Trp

c.397C>T · rs561386590 · VCV2569673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2381	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -12.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.33	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.84	GERP -5.5
Regional constraint	o/e 1.00	unconstrained · MANE · 437 bp · p 0.98 · regional, not allelic
Overall
CADD	23.7	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 0.00226% East Asian · 1/44,322 alleles

Filtering AF 0.000806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000653%

Overall 0.00139% 20/1,440,200 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,322
Finnishnot grpmax-eligible	0.00188%	53,284
Remaining individualsnot grpmax-eligible	0.00162%	61,902
European (non-Finnish)	0.00136%	73,407
South Asian	0.00112%	89,072

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: CALML5
Protein: p.Arg133Trp
Coding: c.397C>T
MANE Select: NM_017422
dbSNP: rs561386590
Type: single nucleotide variant
Location: chr10:5499042 (GRCh38)
Gene constraint: LOEUF 1.883 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 81.24 · 1 PDB
Residue 133: a binding site; a β-strand; the ef-hand 4 domain

Full CALML5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALML5 p.Arg133Leu Uncertain significance ★ ⚠ same residue
CALML5 p.Ala106Gly Uncertain significance ★ ⚠ same type
CALML5 p.Ala16Thr Uncertain significance ★ ⚠ same type
CALML5 p.Ala47Thr Uncertain significance ★ ⚠ same type
CALML5 p.Ala89Gly Uncertain significance ★ ⚠ same type
CALML5 p.Arg105Pro Uncertain significance ★ ⚠ same type
CALML5 p.Asp23Glu Uncertain significance ★ ⚠ same type
CALML5 p.Asp59Ala 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/calml5-p-arg133trp (accessed [today's date]).

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