Is HDAC6 p.Arg17Ser (c.51G>C) pathogenic?

HDAC6 p.Arg17Ser (c.51G>C) is classified Uncertain significance in HDAC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.4763); Ultra-rare (popmax 0.0808%, afr).

How common is HDAC6 p.Arg17Ser (c.51G>C) in the general population?

HDAC6 p.Arg17Ser (c.51G>C) is ultra-rare (popmax 0.0808%, afr) (gnomAD).

What do computational predictors say about HDAC6 p.Arg17Ser (c.51G>C)?

AlphaMissense predicts ambiguous (score 0.4763) — an in-silico prediction, not a clinical call.

HDAC6 p.Arg17Ser

c.51G>C · rs375722411 · VCV2356503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0808%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4763	ambiguous
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.91	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 0.071	GERP -2.9, phastCons 0.73
Regional constraint	o/e 0.75	unconstrained · MANE · 12 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	15.24	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0808% African / African-American · 46/56,947 alleles

Filtering AF 0.0622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0556%

Overall 0.00389% 47/1,207,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0808%	1,238
Remaining individualsnot grpmax-eligible	0.0021%	47,533

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: HDAC6
Protein: p.Arg17Ser
Coding: c.51G>C
MANE Select: NM_006044
dbSNP: rs375722411
Type: single nucleotide variant
Location: chrX:48802743 (GRCh38)
Structure: AlphaFold pLDDT 77.66 · 22 PDB
Residue 17: the 'disordered' 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-arg17ser (accessed [today's date]).

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