Is INTS6 p.His400Arg (c.1199A>G) pathogenic?

INTS6 p.His400Arg (c.1199A>G) is classified Pathogenic in INTS6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-06-18). AlphaMissense: likely pathogenic (0.9085); Absent from gnomAD v4.1; Associated with INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 78.

What condition is associated with INTS6 p.His400Arg (c.1199A>G)?

INTS6 p.His400Arg (c.1199A>G) is associated with INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 78 (ClinVar).

How common is INTS6 p.His400Arg (c.1199A>G) in the general population?

INTS6 p.His400Arg (c.1199A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INTS6 p.His400Arg (c.1199A>G)?

AlphaMissense predicts likely pathogenic (score 0.9085) — an in-silico prediction, not a clinical call.

INTS6 p.His400Arg

c.1199A>G · VCV4856427

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9085 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 78

Computational evidence

Protein change
AlphaMissense	0.9085	likely pathogenic ✓ concordant with ClinVar
REVEL	0.514	indeterminate
SaProt	LLR -13.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 17 kb · p 5.9e-28 · regional, not allelic
Overall
CADD	26.0	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

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.His400Arg
Coding: c.1199A>G
MANE Select: NM_012141
Type: single nucleotide variant
Location: chr13:51382105 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.80 · 9 PDB
Residue 400: a β-strand

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

Disease context

INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 78 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS6 p.Thr137Ile Pathogenic ⚠ same condition
INTS6 c.613+3_613+6del Pathogenic same condition
INTS6 p.Thr749Ala Benign ★★ same type
INTS6 p.Arg206Cys Likely pathogenic ★ same type
INTS6 p.Arg610Ter Pathogenic ★ same type
INTS6 p.Gln185Ter Pathogenic ★ same type
INTS6 p.Gln228Glu Likely pathogenic ★ same type
INTS6 c.613+2T>C 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/ints6-p-his400arg (accessed [today's date]).

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