Is UNC45A p.Ala708Val (c.2123C>T) pathogenic?

UNC45A p.Ala708Val (c.2123C>T) is classified Uncertain significance in UNC45A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.8681); Very rare (popmax 0.00489%, eas); Associated with Inborn genetic diseases.

What condition is associated with UNC45A p.Ala708Val (c.2123C>T)?

UNC45A p.Ala708Val (c.2123C>T) is associated with Inborn genetic diseases (ClinVar).

How common is UNC45A p.Ala708Val (c.2123C>T) in the general population?

UNC45A p.Ala708Val (c.2123C>T) is very rare (popmax 0.00489%, eas) (gnomAD).

What do computational predictors say about UNC45A p.Ala708Val (c.2123C>T)?

AlphaMissense predicts likely pathogenic (score 0.8681) — an in-silico prediction, not a clinical call.

UNC45A p.Ala708Val

c.2123C>T · rs377763973 · VCV3186547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00489%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8681	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -14.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00489% East Asian · 2/40,940 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.000451% 7/1,551,624 alleles · very rare exomes 4/1,399,384 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00489%	20,470
African / African-American	0.00411%	24,354
Remaining individualsnot grpmax-eligible	0.00166%	60,094
European (non-Finnish)	8.72e-05%	1,147,017

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.Ala708Val
Coding: c.2123C>T
MANE Select: NM_018671
dbSNP: rs377763973
Type: single nucleotide variant
Location: chr15:90950203 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 708: a UniProt-annotated variant site (in oohe; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UNC45A p.Ala214Val Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala371Thr Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala386Val Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala428Thr Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala592Val Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala711Thr Uncertain significance ★★ ⚠ same condition
UNC45A p.Ala761Thr Uncertain significance ★★ ⚠ same condition
UNC45A p.Arg107Gly Uncertain significance ★★ ⚠ 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/unc45a-p-ala708val (accessed [today's date]).

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