Is UNC45A p.Pro6fs (c.14dup) pathogenic?

UNC45A p.Pro6fs (c.14dup) is classified Uncertain significance in UNC45A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). Ultra-rare (popmax 0.0122%, sas).

How common is UNC45A p.Pro6fs (c.14dup) in the general population?

UNC45A p.Pro6fs (c.14dup) is ultra-rare (popmax 0.0122%, sas) (gnomAD).

UNC45A p.Pro6fs

c.14dup · rs779389853 · VCV1955253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP 2.3, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% South Asian · 11/90,364 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00526%

Overall 0.000686% 11/1,604,308 alleles · ultra-rare exomes 10/1,452,540 · genomes 1/151,768 · joint denominator

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: UNC45A
Protein: p.Pro6fs
Coding: c.14dup
MANE Select: NM_018671
dbSNP: rs779389853
Type: Duplication
Location: chr15:90935336 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 6: the 'disordered' region

Full UNC45A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UNC45A p.Ala256fs Conflicting classifications of pathogenicity ★ same type
UNC45A p.Ile283fs Uncertain significance ★ same type
UNC45A c.2007-18dup Benign ★ 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/unc45a-p-pro6fs (accessed [today's date]).

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