Is UNC45A p.Ser436Arg (c.1306A>C) pathogenic?

UNC45A p.Ser436Arg (c.1306A>C) is classified Uncertain significance in UNC45A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.2568); Very rare (popmax 0.00441%, nfe); Associated with Inborn genetic diseases.

What condition is associated with UNC45A p.Ser436Arg (c.1306A>C)?

UNC45A p.Ser436Arg (c.1306A>C) is associated with Inborn genetic diseases (ClinVar).

How common is UNC45A p.Ser436Arg (c.1306A>C) in the general population?

UNC45A p.Ser436Arg (c.1306A>C) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about UNC45A p.Ser436Arg (c.1306A>C)?

AlphaMissense predicts likely benign (score 0.2568) — an in-silico prediction, not a clinical call.

UNC45A p.Ser436Arg

c.1306A>C · VCV4196176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2568	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.68	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 5.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.36 · regional, not allelic
Overall
CADD	21.8	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 0.00441% European (non-Finnish) · 52/1,180,028 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00335% 54/1,613,324 alleles · very rare exomes 52/1,461,146 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,693
Remaining individualsnot grpmax-eligible	0.0032%	31,208

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.Ser436Arg
Coding: c.1306A>C
MANE Select: NM_018671
Type: single nucleotide variant
Location: chr15:90946720 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.36 · 1 PDB
Residue 436: 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.Ser436= Likely benign ★★ same residue
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

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-ser436arg (accessed [today's date]).

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