Is INTS9 p.Thr126Met (c.377C>T) pathogenic?

INTS9 p.Thr126Met (c.377C>T) is classified Uncertain significance in INTS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-20). AlphaMissense: likely pathogenic (0.9397); Very rare (popmax 0.0022%, sas).

How common is INTS9 p.Thr126Met (c.377C>T) in the general population?

INTS9 p.Thr126Met (c.377C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about INTS9 p.Thr126Met (c.377C>T)?

AlphaMissense predicts likely pathogenic (score 0.9397) — an in-silico prediction, not a clinical call.

INTS9 p.Thr126Met

c.377C>T · rs369665593 · VCV2261825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9397	likely pathogenic
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -12.91	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 93 kb · p 0.36 · regional, not allelic
Overall
CADD	32.0	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 0.0022% South Asian · 2/91,040 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,613,292 alleles · very rare exomes 18/1,461,148 · genomes 3/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,520
European (non-Finnish)	0.00161%	62,102

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.Thr126Met
Coding: c.377C>T
MANE Select: NM_018250
dbSNP: rs369665593
Type: single nucleotide variant
Location: chr8:28837661 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.95 · 15 PDB

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-thr126met (accessed [today's date]).

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