Is HDAC3 p.Pro400Ser (c.1198C>T) pathogenic?

HDAC3 p.Pro400Ser (c.1198C>T) is classified Uncertain significance in HDAC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.0645); Very rare (popmax 0.00669%, eas).

How common is HDAC3 p.Pro400Ser (c.1198C>T) in the general population?

HDAC3 p.Pro400Ser (c.1198C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about HDAC3 p.Pro400Ser (c.1198C>T)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

HDAC3 p.Pro400Ser

c.1198C>T · VCV3283683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 2.6, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 3,821 bp · p 0.011 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00031% 5/1,612,936 alleles · very rare exomes 5/1,460,708 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Remaining individualsnot grpmax-eligible	0.0032%	31,218

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: HDAC3
Protein: p.Pro400Ser
Coding: c.1198C>T
MANE Select: NM_003883
Type: single nucleotide variant
Location: chr5:141625227 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.73 · 1 PDB
Residue 400: the 'disordered' region

Full HDAC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC3 p.Arg301Gln Likely pathogenic ★ ⚠ same type
HDAC3 p.Arg345His Uncertain significance ★ ⚠ same type
HDAC3 p.Arg352Gly Uncertain significance ★ ⚠ same type
HDAC3 p.Arg406Lys Uncertain significance ★ ⚠ same type
HDAC3 p.Asn287Ser Uncertain significance ★ ⚠ same type
HDAC3 p.Asp93Gly Uncertain significance ★ ⚠ same type
HDAC3 p.Glu317Gly Uncertain significance ★ same type
HDAC3 p.Glu64Gly 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/hdac3-p-pro400ser (accessed [today's date]).

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