Is HDAC7 p.Arg635Cys (c.1903C>T) pathogenic?

HDAC7 p.Arg635Cys (c.1903C>T) is classified Uncertain significance in HDAC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely pathogenic (0.6248); Ultra-rare (popmax 0.0202%, amr).

How common is HDAC7 p.Arg635Cys (c.1903C>T) in the general population?

HDAC7 p.Arg635Cys (c.1903C>T) is ultra-rare (popmax 0.0202%, amr) (gnomAD).

What do computational predictors say about HDAC7 p.Arg635Cys (c.1903C>T)?

AlphaMissense predicts likely pathogenic (score 0.6248) — an in-silico prediction, not a clinical call.

HDAC7 p.Arg635Cys

c.1903C>T · VCV3524463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6248 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6248	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -12.20	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 9.9	GERP -0.58, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,875 bp · p 0.0016 · regional, not allelic
Overall
CADD	31.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R596C vs ClinVar R635C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0202% Admixed American · 12/59,492 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00373% 60/1,609,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0202%	4,958
South Asian	0.00774%	12,922
Remaining individualsnot grpmax-eligible	0.00643%	15,557
European (non-Finnish)	0.00297%	33,662
East Asian	0.00223%	44,792
Finnishnot grpmax-eligible	0.00159%	63,064

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.Arg635Cys
Coding: c.1903C>T
MANE Select: NM_015401
Type: single nucleotide variant
Location: chr12:47791616 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.90 · 6 PDB
Residue 635: an α-helix; the 'histone deacetylase' region

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

Similar variants

HDAC7 p.Arg635His 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-arg635cys (accessed [today's date]).

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