Is UNC45A p.Ala409Val (c.1226C>T) pathogenic?

UNC45A p.Ala409Val (c.1226C>T) is classified Uncertain significance in UNC45A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-21). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00267%, afr).

How common is UNC45A p.Ala409Val (c.1226C>T) in the general population?

UNC45A p.Ala409Val (c.1226C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about UNC45A p.Ala409Val (c.1226C>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

UNC45A p.Ala409Val

c.1226C>T · rs1326203522 · VCV1498516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.92, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.36 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,838 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,609,338 alleles · very rare exomes 1/1,457,100 · genomes 2/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,419
Finnishnot grpmax-eligible	0.00157%	63,790

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.Ala409Val
Coding: c.1226C>T
MANE Select: NM_018671
dbSNP: rs1326203522
Type: single nucleotide variant
Location: chr15:90946640 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 409: 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.Ala409= Likely benign ★ 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-ala409val (accessed [today's date]).

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