Is UNC45B p.Ala554Ser (c.1660G>T) pathogenic?

UNC45B p.Ala554Ser (c.1660G>T) is classified Uncertain significance in UNC45B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-23). AlphaMissense: likely benign (0.1123); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with UNC45B p.Ala554Ser (c.1660G>T)?

UNC45B p.Ala554Ser (c.1660G>T) is associated with Inborn genetic diseases (ClinVar).

How common is UNC45B p.Ala554Ser (c.1660G>T) in the general population?

UNC45B p.Ala554Ser (c.1660G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about UNC45B p.Ala554Ser (c.1660G>T)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

UNC45B p.Ala554Ser

c.1660G>T · rs970516286 · VCV2528826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.11	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 38 kb · p 0.24 · regional, not allelic
Overall
CADD	24.3	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 0.00017% European (non-Finnish) · 2/1,178,810 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,408 alleles · very rare exomes 2/1,460,112 · genomes 0/152,296 · joint denominator

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: UNC45B
Protein: p.Ala554Ser
Coding: c.1660G>T
MANE Select: NM_001267052
dbSNP: rs970516286
Type: single nucleotide variant
Location: chr17:35170226 (GRCh38)
Gene constraint: LOEUF 0.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.38

Full UNC45B 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

UNC45B p.Ala626Gly Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg481Cys Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg622Gln Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg713Gly Uncertain significance ★★ ⚠ same condition
UNC45B p.Arg752Trp Uncertain significance ★★ ⚠ same condition
UNC45B p.Asp902Glu Uncertain significance ★★ ⚠ same condition
UNC45B p.Cys84Phe Uncertain significance ★★ ⚠ same condition
UNC45B p.Gln400His 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/unc45b-p-ala554ser (accessed [today's date]).

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