Is HDAC4 p.Ala37= (c.111G>A) pathogenic?

HDAC4 p.Ala37= (c.111G>A) is classified Benign/Likely benign in HDAC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-28). Rare (popmax 0.984%, sas); Associated with 2q37 microdeletion syndrome.

What condition is associated with HDAC4 p.Ala37= (c.111G>A)?

HDAC4 p.Ala37= (c.111G>A) is associated with 2q37 microdeletion syndrome, neurodevelopmental disorder with central hypotonia and dysmorphic facies (ClinVar).

How common is HDAC4 p.Ala37= (c.111G>A) in the general population?

HDAC4 p.Ala37= (c.111G>A) is rare (popmax 0.984%, sas) (gnomAD).

HDAC4 p.Ala37=

c.111G>A · rs540431173 · VCV774111

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.984%, sas)

Conditions

2q37 microdeletion syndrome

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 -10	GERP -4.7
Overall
CADD	0.432	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.984% South Asian · 895/90,960 alleles

Filtering AF 0.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.909%

Overall 0.0619% 991/1,600,846 alleles · rare exomes 944/1,448,874 · genomes 47/151,972 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.984%	102
Middle Eastern	0.0847%	1,181
Remaining individualsnot grpmax-eligible	0.0706%	1,416
East Asian	0.0357%	2,798
Admixed American	0.00667%	14,981
African / African-American	0.00401%	24,949
European (non-Finnish)	0.00204%	49,126

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: HDAC4
Protein: p.Ala37=
Coding: c.111G>A
MANE Select: NM_001378414
dbSNP: rs540431173
Type: single nucleotide variant
Location: chr2:239190061 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB

Full HDAC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

2q37 microdeletion syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with central hypotonia and dysmorphic facies

Similar variants

HDAC4 p.Pro248Leu Pathogenic ★★ same condition
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same condition
HDAC4 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg535His Uncertain significance ★★ ⚠ same condition
HDAC4 p.Asp982Asn Uncertain significance ★★ same condition
HDAC4 p.Gly793Glu Uncertain significance ★★ ⚠ same condition
HDAC4 p.His556Tyr Uncertain significance ★★ ⚠ same condition
HDAC4 p.Ile766Thr Uncertain significance ★★ ⚠ same condition

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/hdac4-p-ala37 (accessed [today's date]).

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