Is UNC45A p.Pro425= (c.1275A>G) pathogenic?

UNC45A p.Pro425= (c.1275A>G) is classified Benign in UNC45A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 16.2%, sas) — too common for a highly-penetrant pathogenic allele.

UNC45A p.Pro425=

Q: How common is UNC45A p.Pro425= (c.1275A>G) in the general population?

UNC45A p.Pro425= (c.1275A>G) is common (popmax 16.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1275A>G · rs12911432 · VCV1170671

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 16.2%, sas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -4
Overall
CADD	0.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.2% South Asian · 14,777/90,998 alleles

Filtering AF 16% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.9%

Overall 7.23% 116,571/1,612,592 alleles · common exomes 108,103/1,460,280 · genomes 8,468/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	16.2%	6
Amishnot grpmax-eligible	12%	8
Finnishnot grpmax-eligible	8.81%	11
Ashkenazi Jewishnot grpmax-eligible	7.68%	13
European (non-Finnish)	7.31%	14
Remaining individualsnot grpmax-eligible	7.08%	14
Middle Eastern	6.06%	17
Admixed American	3.09%	32
African / African-American	1.14%	88
East Asian	0.138%	724

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.Pro425=
Coding: c.1275A>G
MANE Select: NM_018671
dbSNP: rs12911432
Type: single nucleotide variant
Location: chr15:90946689 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 425: a UniProt-annotated variant site (in oohe; uncertain significance)

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

Similar variants

UNC45A p.Pro425Leu Uncertain significance ★ same residue
UNC45A p.Ala214Val Uncertain significance ★★ ⚠ same type
UNC45A p.Ala371Thr Uncertain significance ★★ ⚠ same type
UNC45A p.Ala386Val Uncertain significance ★★ ⚠ same type
UNC45A p.Ala428Thr Uncertain significance ★★ ⚠ same type
UNC45A p.Ala592Val Uncertain significance ★★ ⚠ same type
UNC45A p.Ala711Thr Uncertain significance ★★ ⚠ same type
UNC45A p.Ala761Thr 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/unc45a-p-pro425 (accessed [today's date]).

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