Is HDAC9 p.Arg445His (c.1334G>A) pathogenic?

HDAC9 p.Arg445His (c.1334G>A) is classified Uncertain significance in HDAC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: ambiguous (0.365); Ultra-rare (popmax 0.0165%, mid).

How common is HDAC9 p.Arg445His (c.1334G>A) in the general population?

HDAC9 p.Arg445His (c.1334G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HDAC9 p.Arg445His (c.1334G>A)?

AlphaMissense predicts ambiguous (score 0.365) — an in-silico prediction, not a clinical call.

HDAC9 p.Arg445His

c.1334G>A · rs764185312 · VCV3104648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.365 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.365	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 19 kb · p 0.55 · regional, not allelic
Overall
CADD	33.0	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 R442H vs ClinVar R445H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00297% 48/1,613,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.005%	19,989
Remaining individualsnot grpmax-eligible	0.0048%	20,824
East Asian	0.00446%	22,397
South Asian	0.00329%	30,353
European (non-Finnish)	0.00288%	34,698
African / African-American	0.00267%	37,469

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.Arg445His
Coding: c.1334G>A
MANE Select: NM_178425
dbSNP: rs764185312
Type: single nucleotide variant
Location: chr7:18648550 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.48 · 2 PDB

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-arg445his (accessed [today's date]).

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