Is INTS8 p.Tyr499Cys (c.1496A>G) pathogenic?

INTS8 p.Tyr499Cys (c.1496A>G) is classified Uncertain significance in INTS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.488); Ultra-rare (popmax 0.0829%, amr); Associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity.

What condition is associated with INTS8 p.Tyr499Cys (c.1496A>G)?

INTS8 p.Tyr499Cys (c.1496A>G) is associated with neurodevelopmental disorder with cerebellar hypoplasia and spasticity (ClinVar).

How common is INTS8 p.Tyr499Cys (c.1496A>G) in the general population?

INTS8 p.Tyr499Cys (c.1496A>G) is ultra-rare (popmax 0.0829%, amr) (gnomAD).

What do computational predictors say about INTS8 p.Tyr499Cys (c.1496A>G)?

AlphaMissense predicts ambiguous (score 0.488) — an in-silico prediction, not a clinical call.

INTS8 p.Tyr499Cys

c.1496A>G · VCV3529497

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.488 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

neurodevelopmental disorder with cerebellar hypoplasia and spasticity

Computational evidence

Protein change
AlphaMissense	0.488	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -6.07	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 57 kb · p 2.4e-07 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0829% Admixed American · 48/57,870 alleles

Filtering AF 0.0642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.00682% 109/1,597,744 alleles · ultra-rare exomes 87/1,445,408 · genomes 22/152,336 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0829%	1,206
Remaining individualsnot grpmax-eligible	0.0226%	4,420
African / African-American	0.0188%	5,319
European (non-Finnish)	0.00264%	37,810
South Asian	0.00228%	43,799

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.Tyr499Cys
Coding: c.1496A>G
MANE Select: NM_017864
Type: single nucleotide variant
Location: chr8:94850080 (GRCh38)
Gene constraint: LOEUF 0.453 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 10 PDB

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 c.1018-11G>A Benign ★★ same condition
INTS8 p.Ala898= 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-tyr499cys (accessed [today's date]).

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