Is UNC45A p.Arg240Pro (c.719G>C) pathogenic?

UNC45A p.Arg240Pro (c.719G>C) is classified Benign in UNC45A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.177); Common (popmax 9.01%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about UNC45A p.Arg240Pro (c.719G>C)?

AlphaMissense predicts likely benign (score 0.177) — an in-silico prediction, not a clinical call.

UNC45A p.Arg240Pro

Q: How common is UNC45A p.Arg240Pro (c.719G>C) in the general population?

UNC45A p.Arg240Pro (c.719G>C) is common (popmax 9.01%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.719G>C · rs145502142 · VCV1166613

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.177 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.01%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.177	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.27	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 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.36 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.01% Admixed American · 5,403/59,978 alleles

Filtering AF 8.81% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.73%

Overall 0.376% 6,062/1,613,862 alleles · common exomes 4,951/1,461,656 · genomes 1,111/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	9.01%	11
Remaining individualsnot grpmax-eligible	0.357%	280
East Asian	0.265%	377
African / African-American	0.0893%	1,120
South Asian	0.0846%	1,182
Finnishnot grpmax-eligible	0.0656%	1,524
European (non-Finnish)	0.0111%	9,007

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.Arg240Pro
Coding: c.719G>C
MANE Select: NM_018671
dbSNP: rs145502142
Type: single nucleotide variant
Location: chr15:90942468 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB

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

Similar variants

UNC45A p.Arg240Trp Uncertain significance ★★ ⚠ same residue
UNC45A p.Arg240Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg240pro (accessed [today's date]).

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