Is UNC45B p.Arg752Trp (c.2254C>T) pathogenic?

UNC45B p.Arg752Trp (c.2254C>T) is classified Uncertain significance in UNC45B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-13). AlphaMissense: likely pathogenic (0.8411); Very rare (popmax 0.00811%, nfe); Associated with Inborn genetic diseases.

What condition is associated with UNC45B p.Arg752Trp (c.2254C>T)?

UNC45B p.Arg752Trp (c.2254C>T) is associated with Inborn genetic diseases (ClinVar).

How common is UNC45B p.Arg752Trp (c.2254C>T) in the general population?

UNC45B p.Arg752Trp (c.2254C>T) is very rare (popmax 0.00811%, nfe) (gnomAD).

What do computational predictors say about UNC45B p.Arg752Trp (c.2254C>T)?

AlphaMissense predicts likely pathogenic (score 0.8411) — an in-silico prediction, not a clinical call.

UNC45B p.Arg752Trp

c.2254C>T · rs779897509 · VCV1410412

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00811%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8411	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -15.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -0.49, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 38 kb · p 0.24 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R754W vs ClinVar R752W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00811% European (non-Finnish) · 93/1,146,784 alleles

Filtering AF 0.00675% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00626%

Overall 0.00619% 96/1,552,020 alleles · very rare exomes 89/1,399,926 · genomes 7/152,094 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00811%	12,331
Remaining individualsnot grpmax-eligible	0.00332%	30,078
African / African-American	0.00137%	73,056

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: UNC45B
Protein: p.Arg752Trp
Coding: c.2254C>T
MANE Select: NM_001267052
dbSNP: rs779897509
Type: single nucleotide variant
Location: chr17:35177609 (GRCh38)
Gene constraint: LOEUF 0.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.38
Residue 754 UniProt numbering: a UniProt-annotated variant site (in mfm11; mislocated away from the a-band to the z-disk)

Full UNC45B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UNC45B p.Arg752Gln Pathogenic ★★ same residue
UNC45B p.Ala626Gly Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg481Cys Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg622Gln Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg713Gly Uncertain significance ★★ ⚠ same condition
UNC45B p.Asp902Glu Uncertain significance ★★ ⚠ same condition
UNC45B p.Cys84Phe Uncertain significance ★★ ⚠ same condition
UNC45B p.Gln400His Uncertain significance ★★ ⚠ same condition

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/unc45b-p-arg752trp (accessed [today's date]).

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