Is INTS8 p.Arg359Ter (c.1075C>T) pathogenic?

INTS8 p.Arg359Ter (c.1075C>T) is classified Likely pathogenic in INTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-18). Very rare (popmax 0.00111%, sas); Associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity.

What condition is associated with INTS8 p.Arg359Ter (c.1075C>T)?

INTS8 p.Arg359Ter (c.1075C>T) is associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity (ClinVar).

How common is INTS8 p.Arg359Ter (c.1075C>T) in the general population?

INTS8 p.Arg359Ter (c.1075C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

INTS8 p.Arg359Ter

c.1075C>T · rs1192451883 · VCV2442176

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Conditions

neurodevelopmental disorder with cerebellar hypoplasia and spasticity

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.31	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.6, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,400 alleles

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

Overall 0.000187% 3/1,608,518 alleles · very rare exomes 2/1,456,446 · genomes 1/152,072 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,400
European (non-Finnish)	0.00017%	588,183

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: INTS8
Protein: p.Arg359Ter
Coding: c.1075C>T
MANE Select: NM_017864
dbSNP: rs1192451883
Type: single nucleotide variant
Location: chr8:94841548 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 359: an α-helix

Full INTS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with cerebellar hypoplasia and spasticity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS8 p.Tyr499Cys Uncertain significance ★★ ⚠ same condition
INTS8 c.1018-11G>A Benign ★★ same condition
INTS8 p.Ala898= Benign ★★ same condition
INTS8 p.Ser710= Benign ★★ same condition
INTS8 p.Gln955Glu Uncertain significance ★ ⚠ same condition
INTS8 p.Asp298Gly Pathogenic same condition
INTS8 p.Glu973_Leu975del Pathogenic same condition
INTS8 p.Gly437Glu Likely benign ★★ same type

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/ints8-p-arg359ter (accessed [today's date]).

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