Is INTS6 p.Val381Gly (c.1142T>G) pathogenic?

INTS6 p.Val381Gly (c.1142T>G) is classified Uncertain significance in INTS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-02). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with INTS6-related disorder.

What condition is associated with INTS6 p.Val381Gly (c.1142T>G)?

INTS6 p.Val381Gly (c.1142T>G) is associated with INTS6-related disorder (ClinVar).

How common is INTS6 p.Val381Gly (c.1142T>G) in the general population?

INTS6 p.Val381Gly (c.1142T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INTS6 p.Val381Gly (c.1142T>G)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

INTS6 p.Val381Gly

c.1142T>G · rs2541651214 · VCV2634125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

INTS6-related disorder

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic · top 9% in INTS6
REVEL	0.654	pathogenic-leaning
SaProt	LLR -17.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 17 kb · p 5.9e-28 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INTS6
Protein: p.Val381Gly
Coding: c.1142T>G
MANE Select: NM_012141
dbSNP: rs2541651214
Type: single nucleotide variant
Location: chr13:51383367 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.80 · 9 PDB
Residue 381: a β-strand

Full INTS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

INTS6-related disorder

Similar variants

INTS6 p.Gln228Glu Likely pathogenic ★ same condition
INTS6 c.1275+1G>A Uncertain significance same condition
INTS6 p.Arg550Ter Uncertain significance same condition
INTS6 p.Gly30= Uncertain significance same condition
INTS6 c.340-3T>C Benign same condition
INTS6 p.Ala738Gly Likely benign same condition
INTS6 p.Asp518= Likely benign same condition
INTS6 p.Leu845= Likely benign same condition

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/ints6-p-val381gly (accessed [today's date]).

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