Is UNC45B p.Arg752Gln (c.2255G>A) pathogenic?

UNC45B p.Arg752Gln (c.2255G>A) is classified Pathogenic in UNC45B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-09). AlphaMissense: ambiguous (0.3719); Ultra-rare (popmax 0.0354%, amr); Associated with UNC45B-related disorder.

What condition is associated with UNC45B p.Arg752Gln (c.2255G>A)?

UNC45B p.Arg752Gln (c.2255G>A) is associated with UNC45B-related disorder, myopathy, myofibrillar myopathy 11 (ClinVar).

How common is UNC45B p.Arg752Gln (c.2255G>A) in the general population?

UNC45B p.Arg752Gln (c.2255G>A) is ultra-rare (popmax 0.0354%, amr) (gnomAD).

What do computational predictors say about UNC45B p.Arg752Gln (c.2255G>A)?

AlphaMissense predicts ambiguous (score 0.3719) — an in-silico prediction, not a clinical call.

UNC45B p.Arg752Gln

c.2255G>A · rs139715157 · VCV834072

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, amr)

Conditions

UNC45B-related disorder

Computational evidence

Protein change
AlphaMissense	0.3719	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -12.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.49	loss · gain 0.43 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 38 kb · p 0.24 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R754Q vs ClinVar R752Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0354% Admixed American · 18/50,906 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00725% 112/1,543,968 alleles · ultra-rare exomes 95/1,391,748 · genomes 17/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0354%	2,828
Remaining individualsnot grpmax-eligible	0.0134%	7,486
European (non-Finnish)	0.00702%	14,250
East Asian	0.00488%	20,482
African / African-American	0.00411%	24,337
Finnishnot grpmax-eligible	0.00167%	59,942

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.Arg752Gln
Coding: c.2255G>A
MANE Select: NM_001267052
dbSNP: rs139715157
Type: single nucleotide variant
Location: chr17:35177610 (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

UNC45B-related disorder

Also linked: myopathy myofibrillar myopathy 11

Similar variants

UNC45B p.Arg752Trp Uncertain significance ★★ ⚠ same residue
UNC45B p.Asp496Val Uncertain significance ★★ ⚠ same condition
UNC45B c.808+39G>A Benign ★★ same condition
UNC45B c.2255+5G>C Likely pathogenic ★ same condition
UNC45B p.Ala25Thr Uncertain significance ★ ⚠ same condition
UNC45B p.Ala597Thr Uncertain significance ★ ⚠ same condition
UNC45B p.Ala700Asp Uncertain significance ★ ⚠ same condition
UNC45B p.Arg776Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg752gln (accessed [today's date]).

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