Is HDAC1 p.Ser421= (c.1263C>T) pathogenic?

HDAC1 p.Ser421= (c.1263C>T) is classified Likely benign in HDAC1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-13). Rare (popmax 0.1%, eas); Associated with HDAC1-related disorder.

What condition is associated with HDAC1 p.Ser421= (c.1263C>T)?

HDAC1 p.Ser421= (c.1263C>T) is associated with HDAC1-related disorder (ClinVar).

How common is HDAC1 p.Ser421= (c.1263C>T) in the general population?

HDAC1 p.Ser421= (c.1263C>T) is rare (popmax 0.1%, eas) (gnomAD).

HDAC1 p.Ser421=

c.1263C>T · rs145425494 · VCV3033900

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Conditions

HDAC1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.1
Overall
CADD	0.159	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% East Asian · 45/44,860 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00627% 101/1,611,964 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	997
African / African-American	0.0307%	3,253
Middle Eastern	0.0166%	6,010
South Asian	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.00962%	10,393
European (non-Finnish)	0.000933%	107,182

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: HDAC1
Protein: p.Ser421=
Coding: c.1263C>T
MANE Select: NM_004964
dbSNP: rs145425494
Type: single nucleotide variant
Location: chr1:32332133 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 12 PDB
Residue 421: the 'disordered' region; a modified residue (phosphoserine; by ck2)

Full HDAC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HDAC1-related disorder

Similar variants

HDAC1 p.Asp234= Benign ★★ same type
HDAC1 p.Tyr188= Benign ★★ same type
HDAC1 p.Asn154Ser Likely pathogenic ★ same type
HDAC1 p.Ala256Thr Uncertain significance ★ ⚠ same type
HDAC1 p.Ala388Thr Uncertain significance ★ ⚠ same type
HDAC1 p.Arg310Gln Uncertain significance ★ ⚠ same type
HDAC1 p.Arg310Trp Uncertain significance ★ ⚠ same type
HDAC1 p.Arg413Gln 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/hdac1-p-ser421 (accessed [today's date]).

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