Is INTS9 p.Tyr182Cys (c.545A>G) pathogenic?

INTS9 p.Tyr182Cys (c.545A>G) is classified Uncertain significance in INTS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-31). AlphaMissense: likely pathogenic (0.8652); Ultra-rare (popmax 0.036%, afr).

How common is INTS9 p.Tyr182Cys (c.545A>G) in the general population?

INTS9 p.Tyr182Cys (c.545A>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about INTS9 p.Tyr182Cys (c.545A>G)?

AlphaMissense predicts likely pathogenic (score 0.8652) — an in-silico prediction, not a clinical call.

INTS9 p.Tyr182Cys

c.545A>G · rs147669870 · VCV2265096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8652	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -12.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 93 kb · p 0.36 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/75,024 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00335% 54/1,613,716 alleles · ultra-rare exomes 42/1,461,426 · genomes 12/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,779
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.008%	12,499
East Asian	0.00223%	44,862
European (non-Finnish)	0.0017%	58,982

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: INTS9
Protein: p.Tyr182Cys
Coding: c.545A>G
MANE Select: NM_018250
dbSNP: rs147669870
Type: single nucleotide variant
Location: chr8:28813556 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.95 · 15 PDB
Residue 182: an α-helix

Full INTS9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS9 p.Leu417Pro Uncertain significance ★★ ⚠ same type
INTS9 p.Ala208Val Uncertain significance ★ ⚠ same type
INTS9 p.Ala286Asp Uncertain significance ★ ⚠ same type
INTS9 p.Ala319Val Uncertain significance ★ ⚠ same type
INTS9 p.Ala506Thr Uncertain significance ★ ⚠ same type
INTS9 p.Ala560Thr Uncertain significance ★ ⚠ same type
INTS9 p.Arg401Cys Uncertain significance ★ ⚠ same type
INTS9 p.Arg401His Uncertain significance ★ ⚠ 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/ints9-p-tyr182cys (accessed [today's date]).

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