Is HDAC4 p.Ser616Pro (c.1846T>C) pathogenic?

HDAC4 p.Ser616Pro (c.1846T>C) is classified Uncertain significance in HDAC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: ambiguous (0.5629); Absent from gnomAD v4.1.

How common is HDAC4 p.Ser616Pro (c.1846T>C) in the general population?

HDAC4 p.Ser616Pro (c.1846T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC4 p.Ser616Pro (c.1846T>C)?

AlphaMissense predicts ambiguous (score 0.5629) — an in-silico prediction, not a clinical call.

HDAC4 p.Ser616Pro

c.1846T>C · rs2152799686 · VCV1706873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5629 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5629	ambiguous
REVEL	0.205	benign-leaning
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 15 kb · p 0.31 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S611P vs ClinVar S616P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HDAC4
Protein: p.Ser616Pro
Coding: c.1846T>C
MANE Select: NM_001378414
dbSNP: rs2152799686
Type: single nucleotide variant
Location: chr2:239111658 (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

Similar variants

HDAC4 p.Pro248Leu Pathogenic ★★ same type
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same type
HDAC4 c.865+8G>A Uncertain significance ★★ same type
HDAC4 p.Ala445Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala620Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala91Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Arg132Trp Uncertain significance ★★ ⚠ same type
HDAC4 p.Arg13Gln 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/hdac4-p-ser616pro (accessed [today's date]).

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