Is UNC80 p.Arg489Cys (c.1465C>T) pathogenic?

UNC80 p.Arg489Cys (c.1465C>T) is classified Uncertain significance in UNC80 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.7773); Ultra-rare (popmax 0.0269%, eas); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

What condition is associated with UNC80 p.Arg489Cys (c.1465C>T)?

UNC80 p.Arg489Cys (c.1465C>T) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (ClinVar).

How common is UNC80 p.Arg489Cys (c.1465C>T) in the general population?

UNC80 p.Arg489Cys (c.1465C>T) is ultra-rare (popmax 0.0269%, eas) (gnomAD).

What do computational predictors say about UNC80 p.Arg489Cys (c.1465C>T)?

AlphaMissense predicts likely pathogenic (score 0.7773) — an in-silico prediction, not a clinical call.

UNC80 p.Arg489Cys

Q: How is Hypotonia-speech impairment-severe cognitive delay syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1465C>T · rs773432779 · VCV1403266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0269%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Computational evidence

Protein change
AlphaMissense	0.7773	likely pathogenic
REVEL	0.159	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 57 kb · p 0.0051 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0269% East Asian · 11/40,930 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.00361% 56/1,551,592 alleles · ultra-rare exomes 54/1,399,478 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0269%	3,721
Remaining individualsnot grpmax-eligible	0.00832%	12,021
South Asian	0.00714%	14,010
African / African-American	0.00685%	14,602
Admixed American	0.00392%	25,488
European (non-Finnish)	0.00235%	42,482

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: UNC80
Protein: p.Arg489Cys
Coding: c.1465C>T
MANE Select: NM_001371986
dbSNP: rs773432779
Type: single nucleotide variant
Location: chr2:209817038 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full UNC80 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypotonia, infantile, with psychomotor retardation and characteristic facies 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

UNC80 c.4110+1G>C Pathogenic/Likely pathogenic ★★ same condition
UNC80 c.8772+1G>A Likely pathogenic ★★ same condition
UNC80 p.Arg1076Ter Pathogenic ★★ same condition
UNC80 p.Arg1110Ter Pathogenic ★★ same condition
UNC80 p.Arg1285Ter Pathogenic ★★ same condition
UNC80 p.Arg1355Ter Pathogenic ★★ same condition
UNC80 p.Arg137Ter Pathogenic ★★ same condition
UNC80 p.Arg174Ter Pathogenic ★★ 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/unc80-p-arg489cys (accessed [today's date]).

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