Is UNC80 p.Arg1007Pro (c.3020G>C) pathogenic?

UNC80 p.Arg1007Pro (c.3020G>C) is classified Uncertain significance in UNC80 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-03-15). AlphaMissense: ambiguous (0.4024); Very rare (popmax 0.00589%, amr); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

What condition is associated with UNC80 p.Arg1007Pro (c.3020G>C)?

UNC80 p.Arg1007Pro (c.3020G>C) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (ClinVar).

How common is UNC80 p.Arg1007Pro (c.3020G>C) in the general population?

UNC80 p.Arg1007Pro (c.3020G>C) is very rare (popmax 0.00589%, amr) (gnomAD).

What do computational predictors say about UNC80 p.Arg1007Pro (c.3020G>C)?

AlphaMissense predicts ambiguous (score 0.4024) — an in-silico prediction, not a clinical call.

UNC80 p.Arg1007Pro

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.3020G>C · rs202138404 · VCV1028451

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00589%, amr)

Conditions

hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Computational evidence

Protein change
AlphaMissense	0.4024	ambiguous
REVEL	0.226	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.29	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	25.8	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 0.00589% Admixed American · 3/50,938 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00399%

Overall 0.00439% 68/1,550,380 alleles · very rare exomes 64/1,398,230 · genomes 4/152,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00589%	16,979
European (non-Finnish)	0.0055%	18,194
Remaining individualsnot grpmax-eligible	0.00166%	60,112
South Asian	0.00119%	84,020

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.Arg1007Pro
Coding: c.3020G>C
MANE Select: NM_001371986
dbSNP: rs202138404
Type: single nucleotide variant
Location: chr2:209834989 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1007: the 'disordered' region

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.Arg1007Cys Uncertain significance ★★ ⚠ same residue
UNC80 p.Arg1007His 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

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-arg1007pro (accessed [today's date]).

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