Is HDAC7 p.Ser565Leu (c.1694C>T) pathogenic?

HDAC7 p.Ser565Leu (c.1694C>T) is classified Uncertain significance in HDAC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.2916); Ultra-rare (popmax 0.0295%, nfe).

How common is HDAC7 p.Ser565Leu (c.1694C>T) in the general population?

HDAC7 p.Ser565Leu (c.1694C>T) is ultra-rare (popmax 0.0295%, nfe) (gnomAD).

What do computational predictors say about HDAC7 p.Ser565Leu (c.1694C>T)?

AlphaMissense predicts likely benign (score 0.2916) — an in-silico prediction, not a clinical call.

HDAC7 p.Ser565Leu

c.1694C>T · VCV3524461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2916 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0295%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2916	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -12.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,875 bp · p 0.0016 · regional, not allelic
Overall
CADD	29.8	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 S526L vs ClinVar S565L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0295% European (non-Finnish) · 348/1,177,894 alleles

Filtering AF 0.0269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0259%

Overall 0.0233% 375/1,609,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0295%	3,385
East Asian	0.0112%	8,958
Admixed American	0.01%	9,966
Remaining individualsnot grpmax-eligible	0.00803%	12,454
African / African-American	0.00668%	14,965
South Asian	0.00441%	22,682
Finnishnot grpmax-eligible	0.00317%	31,537

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: HDAC7
Protein: p.Ser565Leu
Coding: c.1694C>T
MANE Select: NM_015401
Type: single nucleotide variant
Location: chr12:47791989 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.90 · 6 PDB
Residue 565: a β-strand; the 'histone deacetylase' region

Full HDAC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC7 p.Ser565Trp Uncertain significance ★ ⚠ same residue
HDAC7 p.Arg201= Benign/Likely benign ★★ same type
HDAC7 p.Leu233= Benign/Likely benign ★★ same type
HDAC7 p.Thr243= Benign ★★ same type
HDAC7 p.Ala138Val Uncertain significance ★ ⚠ same type
HDAC7 p.Ala266Val Uncertain significance ★ ⚠ same type
HDAC7 p.Ala337Gly Uncertain significance ★ ⚠ same type
HDAC7 p.Ala337Thr 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/hdac7-p-ser565leu (accessed [today's date]).

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