Is INTS8 p.Ala898= (c.2694C>T) pathogenic?

INTS8 p.Ala898= (c.2694C>T) is classified Benign in INTS8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-08-19). Common (popmax 64.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity.

What condition is associated with INTS8 p.Ala898= (c.2694C>T)?

INTS8 p.Ala898= (c.2694C>T) is associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity (ClinVar).

INTS8 p.Ala898=

Q: How common is INTS8 p.Ala898= (c.2694C>T) in the general population?

INTS8 p.Ala898= (c.2694C>T) is common (popmax 64.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2694C>T · rs1129152 · VCV1300114

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 64.7%, eas) — too common for a highly-penetrant pathogenic allele

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.
REVEL	0.03	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -1.8, phastCons 1
Overall
CADD	9.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 64.7% East Asian · 28,876/44,612 alleles

Filtering AF 64.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.8%

Overall 42.9% 681,715/1,590,646 alleles · common exomes 621,578/1,438,730 · genomes 60,137/151,916 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	64.7%	2
Admixed American	55.1%	2
South Asian	53.3%	2
Amishnot grpmax-eligible	52.4%	2
Remaining individualsnot grpmax-eligible	44%	2
Middle Eastern	42.3%	2
Ashkenazi Jewishnot grpmax-eligible	42%	2
Finnishnot grpmax-eligible	41.7%	2
European (non-Finnish)	41.6%	2
African / African-American	27.7%	4

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.Ala898=
Coding: c.2694C>T
MANE Select: NM_017864
dbSNP: rs1129152
Type: single nucleotide variant
Location: chr8:94876079 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB
Residue 898: 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.Ser710= Benign ★★ same condition
INTS8 p.Arg359Ter Likely pathogenic ★ 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-ala898 (accessed [today's date]).

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