Is HDAC9 p.Gln665Arg (c.1994A>G) pathogenic?

HDAC9 p.Gln665Arg (c.1994A>G) is classified Uncertain significance in HDAC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: ambiguous (0.3983); Very rare (popmax 0.00167%, amr).

How common is HDAC9 p.Gln665Arg (c.1994A>G) in the general population?

HDAC9 p.Gln665Arg (c.1994A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about HDAC9 p.Gln665Arg (c.1994A>G)?

AlphaMissense predicts ambiguous (score 0.3983) — an in-silico prediction, not a clinical call.

HDAC9 p.Gln665Arg

c.1994A>G · VCV3524489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.3983	ambiguous
REVEL	0.589	indeterminate
SaProt	LLR -10.30	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 247 kb · p 5.3e-07 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q662R vs ClinVar Q665R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,960 alleles

Overall 0.000274% 4/1,461,476 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,341
Admixed Americangrpmax	0.00167%	59,960

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HDAC9
Protein: p.Gln665Arg
Coding: c.1994A>G
MANE Select: NM_178425
Type: single nucleotide variant
Location: chr7:18749089 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.48 · 2 PDB
Residue 665: the 'histone deacetylase' region

Full HDAC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC9 p.Pro390= Benign ★★ same type
HDAC9 c.1910-2A>G Uncertain significance ★ same type
HDAC9 p.Ala1028Val Uncertain significance ★ same type
HDAC9 p.Ala1068Val Uncertain significance ★ same type
HDAC9 p.Ala140Ser Uncertain significance ★ ⚠ same type
HDAC9 p.Ala238Thr Uncertain significance ★ ⚠ same type
HDAC9 p.Ala339Ser Uncertain significance ★ ⚠ same type
HDAC9 p.Ala346Thr 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/hdac9-p-gln665arg (accessed [today's date]).

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