Is HDAC2 p.Pro378Ser (c.1132C>T) pathogenic?

HDAC2 p.Pro378Ser (c.1132C>T) is classified Uncertain significance in HDAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.9906); No allele count reported in gnomAD v4.1 (AN 1,608,958).

How common is HDAC2 p.Pro378Ser (c.1132C>T) in the general population?

HDAC2 p.Pro378Ser (c.1132C>T) is no allele count reported in gnomAD v4.1 (AN 1,608,958) (gnomAD).

What do computational predictors say about HDAC2 p.Pro378Ser (c.1132C>T)?

AlphaMissense predicts likely pathogenic (score 0.9906) — an in-silico prediction, not a clinical call.

HDAC2 p.Pro378Ser

c.1132C>T · VCV4675166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9906 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,608,958)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9906	likely pathogenic
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -10.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 27 kb · p 1.6e-48 · regional, not allelic
Overall
CADD	33.0	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 1,608,958). 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: HDAC2
Protein: p.Pro378Ser
Coding: c.1132C>T
MANE Select: NM_001527
Type: single nucleotide variant
Location: chr6:113944370 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 86.01 · 48 PDB

Full HDAC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC2 p.Ala320Gly Uncertain significance ★ ⚠ same type
HDAC2 p.Arg78Gln Uncertain significance ★ ⚠ same type
HDAC2 p.Asp182Gly Uncertain significance ★ ⚠ same type
HDAC2 p.Asp234Tyr Uncertain significance ★ ⚠ same type
HDAC2 p.Asp423Asn Uncertain significance ★ ⚠ same type
HDAC2 p.Asp465Glu Uncertain significance ★ ⚠ same type
HDAC2 p.Cys262Tyr Uncertain significance ★ ⚠ same type
HDAC2 p.Gln240His 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/hdac2-p-pro378ser (accessed [today's date]).

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