Is HDAC7 p.Pro183Leu (c.548C>T) pathogenic?

HDAC7 p.Pro183Leu (c.548C>T) is classified Uncertain significance in HDAC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0164%, mid).

How common is HDAC7 p.Pro183Leu (c.548C>T) in the general population?

HDAC7 p.Pro183Leu (c.548C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about HDAC7 p.Pro183Leu (c.548C>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

HDAC7 p.Pro183Leu

c.548C>T · rs375989920 · VCV2390623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,875 bp · p 0.0016 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 P144L vs ClinVar P183L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00173% 28/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,459
European (non-Finnish)	0.00195%	51,306

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.Pro183Leu
Coding: c.548C>T
MANE Select: NM_015401
dbSNP: rs375989920
Type: single nucleotide variant
Location: chr12:47797413 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.90 · 6 PDB
Residue 183: the 'transcription repression 1' region; the 'disordered' region

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

Similar variants

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
HDAC7 p.Ala431Gly 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-pro183leu (accessed [today's date]).

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