Is CALML4 p.Arg151Trp (c.451C>T) pathogenic?

CALML4 p.Arg151Trp (c.451C>T) is classified Uncertain significance in CALML4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.219); Ultra-rare (popmax 0.0164%, mid).

How common is CALML4 p.Arg151Trp (c.451C>T) in the general population?

CALML4 p.Arg151Trp (c.451C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CALML4 p.Arg151Trp (c.451C>T)?

AlphaMissense predicts likely benign (score 0.219) — an in-silico prediction, not a clinical call.

CALML4 p.Arg151Trp

c.451C>T · VCV4218359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.219 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.219	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -9.56	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 2.4	GERP -2.9, phastCons 0.049
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.56 · regional, not allelic
Overall
CADD	13.78	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R194W vs ClinVar R151W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00608% 98/1,612,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00721%	13,869
East Asian	0.00668%	14,959
Remaining individualsnot grpmax-eligible	0.00641%	15,609
African / African-American	0.00267%	37,439
South Asian	0.0022%	45,534
Admixed American	0.00167%	59,992

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: CALML4
Protein: p.Arg151Trp
Coding: c.451C>T
MANE Select: NM_033429
Type: single nucleotide variant
Location: chr15:68194026 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.70
Residue 151: the ef-hand 3 domain

Full CALML4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALML4 c.-23C>G Uncertain significance ★ ⚠ same type
CALML4 c.-69G>A Uncertain significance ★ ⚠ same type
CALML4 p.Arg107Trp Uncertain significance ★ ⚠ same type
CALML4 p.Asn134Asp Uncertain significance ★ ⚠ same type
CALML4 p.Asp8Tyr Uncertain significance ★ ⚠ same type
CALML4 p.Asp94Asn Uncertain significance ★ ⚠ same type
CALML4 p.Gln50Arg Uncertain significance ★ ⚠ same type
CALML4 p.Gln79Glu 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/calml4-p-arg151trp (accessed [today's date]).

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