Is UNC45A p.Ala40Asp (c.119C>A) pathogenic?

UNC45A p.Ala40Asp (c.119C>A) is classified Conflicting classifications of pathogenicity in UNC45A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-26). AlphaMissense: likely pathogenic (0.9923); Very rare (popmax 8.48e-05%, nfe); Associated with osteootohepatoenteric syndrome.

What condition is associated with UNC45A p.Ala40Asp (c.119C>A)?

UNC45A p.Ala40Asp (c.119C>A) is associated with osteootohepatoenteric syndrome (ClinVar).

How common is UNC45A p.Ala40Asp (c.119C>A) in the general population?

UNC45A p.Ala40Asp (c.119C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about UNC45A p.Ala40Asp (c.119C>A)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

UNC45A p.Ala40Asp

c.119C>A · rs2151353536 · VCV1476282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

osteootohepatoenteric syndrome

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic · top 2% in UNC45A
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -17.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.36 · regional, not allelic
Overall
CADD	29.3	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 8.48e-05% European (non-Finnish) · 1/1,179,706 alleles

Overall 6.84e-05% 1/1,460,968 alleles · very rare

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.Ala40Asp
Coding: c.119C>A
MANE Select: NM_018671
dbSNP: rs2151353536
Type: single nucleotide variant
Location: chr15:90935611 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 40: an α-helix

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

Disease context

osteootohepatoenteric syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UNC45A p.Met723Ile Uncertain significance ★★ ⚠ same condition
UNC45A c.1027+1G>A Likely pathogenic ★ same condition
UNC45A c.213+1G>C Likely pathogenic ★ same condition
UNC45A c.1500+1G>A Uncertain significance ★ same condition
UNC45A p.Arg241Ter Uncertain significance ★ same condition
UNC45A p.Arg98Trp Uncertain significance ★ ⚠ same condition
UNC45A p.Leu237Pro Uncertain significance ★ ⚠ same condition
UNC45A p.Val438Asp 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-ala40asp (accessed [today's date]).

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