Is HDAC8 p.Leu346Pro (c.1037T>C) pathogenic?

HDAC8 p.Leu346Pro (c.1037T>C) is classified Likely pathogenic in HDAC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-13). AlphaMissense: likely pathogenic (0.9883); No allele count reported in gnomAD v4.1 (AN 1,210,034).

How common is HDAC8 p.Leu346Pro (c.1037T>C) in the general population?

HDAC8 p.Leu346Pro (c.1037T>C) is no allele count reported in gnomAD v4.1 (AN 1,210,034) (gnomAD).

What do computational predictors say about HDAC8 p.Leu346Pro (c.1037T>C)?

AlphaMissense predicts likely pathogenic (score 0.9883) — an in-silico prediction, not a clinical call.

HDAC8 p.Leu346Pro

c.1037T>C · rs1057524379 · VCV392167

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9883 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,210,034)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9883	likely pathogenic ✓ concordant with ClinVar
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -16.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 113 kb · p 4.8e-08 · regional, not allelic
Overall
CADD	26.8	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

No allele count reported in gnomAD v4.1 (AN 1,210,034). 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: HDAC8
Protein: p.Leu346Pro
Coding: c.1037T>C
MANE Select: NM_018486
dbSNP: rs1057524379
Type: single nucleotide variant
Location: chrX:72351807 (GRCh38)
Structure: AlphaFold pLDDT 95.45 · 53 PDB

Full HDAC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC8 c.165-2A>G Pathogenic ★★ same type
HDAC8 c.738-1G>A Pathogenic ★★ same type
HDAC8 c.738-2A>G Pathogenic/Likely pathogenic ★★ same type
HDAC8 p.Ala188Thr Pathogenic/Likely pathogenic ★★ same type
HDAC8 p.Arg164Ter Pathogenic ★★ same type
HDAC8 p.Arg166Ter Pathogenic ★★ same type
HDAC8 p.Arg313Ter Pathogenic ★★ same type
HDAC8 p.Arg37Gln Pathogenic/Likely pathogenic ★★ 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/hdac8-p-leu346pro (accessed [today's date]).

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