Is HDAC6 p.Arg14Pro (c.41G>C) pathogenic?

HDAC6 p.Arg14Pro (c.41G>C) is classified Uncertain significance in HDAC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.4075); Very rare (popmax 0.000559%, nfe).

How common is HDAC6 p.Arg14Pro (c.41G>C) in the general population?

HDAC6 p.Arg14Pro (c.41G>C) is very rare (popmax 0.000559%, nfe) (gnomAD).

What do computational predictors say about HDAC6 p.Arg14Pro (c.41G>C)?

AlphaMissense predicts ambiguous (score 0.4075) — an in-silico prediction, not a clinical call.

HDAC6 p.Arg14Pro

c.41G>C · VCV4034091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000559%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4075	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.56, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 12 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	23.7	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 0.000559% European (non-Finnish) · 5/894,189 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000414% 5/1,208,981 alleles · very rare exomes 5/1,096,012 · genomes 0/112,969 · joint denominator

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.Arg14Pro
Coding: c.41G>C
MANE Select: NM_006044
Type: single nucleotide variant
Location: chrX:48802733 (GRCh38)
Structure: AlphaFold pLDDT 77.66 · 22 PDB
Residue 14: 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-arg14pro (accessed [today's date]).

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