Is UNC80 p.Ala2863= (c.8589G>A) pathogenic?

UNC80 p.Ala2863= (c.8589G>A) is classified Benign/Likely benign in UNC80 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.22%, afr); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

What condition is associated with UNC80 p.Ala2863= (c.8589G>A)?

UNC80 p.Ala2863= (c.8589G>A) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (ClinVar).

How common is UNC80 p.Ala2863= (c.8589G>A) in the general population?

UNC80 p.Ala2863= (c.8589G>A) is low-frequency (popmax 1.22%, afr) (gnomAD).

UNC80 p.Ala2863=

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.8589G>A · rs192024023 · VCV791886

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, afr)

Conditions

hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -5.7
Overall
CADD	0.026	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.22% African / African-American · 891/73,040 alleles

Filtering AF 1.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.13%

Overall 0.074% 1,148/1,550,594 alleles · low-frequency exomes 652/1,398,322 · genomes 496/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.22%	82
East Asian	0.313%	319
Middle Eastern	0.151%	663
Remaining individualsnot grpmax-eligible	0.09%	1,112
Admixed American	0.069%	1,449
South Asian	0.00833%	12,003
European (non-Finnish)	0.00209%	47,773

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.Ala2863=
Coding: c.8589G>A
MANE Select: NM_001371986
dbSNP: rs192024023
Type: single nucleotide variant
Location: chr2:209976120 (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 p.Ala2863Val Uncertain significance ★ same residue
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

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-ala2863 (accessed [today's date]).

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