Is HDAC6 p.Pro213Ser (c.637C>T) pathogenic?

HDAC6 p.Pro213Ser (c.637C>T) is classified Uncertain significance in HDAC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.8645); No allele count reported in gnomAD v4.1 (AN 1,200,878).

How common is HDAC6 p.Pro213Ser (c.637C>T) in the general population?

HDAC6 p.Pro213Ser (c.637C>T) is no allele count reported in gnomAD v4.1 (AN 1,200,878) (gnomAD).

What do computational predictors say about HDAC6 p.Pro213Ser (c.637C>T)?

AlphaMissense predicts likely pathogenic (score 0.8645) — an in-silico prediction, not a clinical call.

HDAC6 p.Pro213Ser

c.637C>T · VCV4269333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8645 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,200,878)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8645	likely pathogenic
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -11.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 12 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	24.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,200,878). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HDAC6
Protein: p.Pro213Ser
Coding: c.637C>T
MANE Select: NM_006044
Type: single nucleotide variant
Location: chrX:48808037 (GRCh38)
Structure: AlphaFold pLDDT 77.66 · 22 PDB
Residue 213: the 'histone deacetylase 1' region

Full HDAC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC6 p.Ala374Gly Uncertain significance ★★ ⚠ same type
HDAC6 c.1059+6G>C Likely benign ★★ same type
HDAC6 c.2187+20G>A Benign ★★ same type
HDAC6 p.Glu1017= Benign/Likely benign ★★ same type
HDAC6 p.Glu889= Benign ★★ same type
HDAC6 p.Gly1051= Benign/Likely benign ★★ same type
HDAC6 p.Gly1083Asp Likely benign ★★ same type
HDAC6 p.Gly930Arg Likely benign ★★ 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/hdac6-p-pro213ser (accessed [today's date]).

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