Is INTS9 p.Val393Leu (c.1177G>T) pathogenic?

INTS9 p.Val393Leu (c.1177G>T) is classified Uncertain significance in INTS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: ambiguous (0.5198); Ultra-rare (popmax 0.0667%, amr).

How common is INTS9 p.Val393Leu (c.1177G>T) in the general population?

INTS9 p.Val393Leu (c.1177G>T) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about INTS9 p.Val393Leu (c.1177G>T)?

AlphaMissense predicts ambiguous (score 0.5198) — an in-silico prediction, not a clinical call.

INTS9 p.Val393Leu

c.1177G>T · VCV3286261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5198	ambiguous
REVEL	0.181	moderately benign-leaning
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 0.97, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 19 kb · p 5.8e-07 · regional, not allelic
Overall
CADD	21.9	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 0.0667% Admixed American · 40/60,006 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.00322% 52/1,613,864 alleles · ultra-rare exomes 26/1,461,678 · genomes 26/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
Middle Eastern	0.0165%	6,066
Remaining individualsnot grpmax-eligible	0.0064%	15,619
African / African-American	0.00133%	74,908
South Asian	0.0011%	91,074
European (non-Finnish)	0.000424%	235,975

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.Val393Leu
Coding: c.1177G>T
MANE Select: NM_018250
Type: single nucleotide variant
Location: chr8:28780916 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.95 · 15 PDB
Residue 393: a β-strand

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-val393leu (accessed [today's date]).

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