Is SIN3B p.Ser504Leu (c.1511C>T) pathogenic?

SIN3B p.Ser504Leu (c.1511C>T) is classified Uncertain significance in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.9419); Very rare (popmax 0.00133%, afr).

How common is SIN3B p.Ser504Leu (c.1511C>T) in the general population?

SIN3B p.Ser504Leu (c.1511C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SIN3B p.Ser504Leu (c.1511C>T)?

AlphaMissense predicts likely pathogenic (score 0.9419) — an in-silico prediction, not a clinical call.

SIN3B p.Ser504Leu

c.1511C>T · VCV4165391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9419	likely pathogenic
REVEL	0.417	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 4,074 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	25.9	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S536L vs ClinVar S504L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,800 alleles · very rare exomes 3/1,461,672 · genomes 0/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,988
European (non-Finnish)	0.00017%	589,936

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: SIN3B
Protein: p.Ser504Leu
Coding: c.1511C>T
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16865537 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 536 UniProt numbering: the 'hdac-interacting domain' region; the 'interaction with ncor1' region; the 'interaction with suds3 and hdac1' region

Full SIN3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIN3B p.Ala534Thr Uncertain significance ★★ same type
SIN3B p.Glu258Asp Uncertain significance ★★ ⚠ same type
SIN3B p.His91Tyr Uncertain significance ★★ ⚠ same type
SIN3B p.Pro281Ala Uncertain significance ★★ ⚠ same type
SIN3B p.Val160Met Uncertain significance ★★ ⚠ same type
SIN3B p.Val873Ile Uncertain significance ★★ ⚠ same type
SIN3B c.1266+354G>A Benign ★★ same type
SIN3B c.2954+6A>G Benign ★★ 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/sin3b-p-ser504leu (accessed [today's date]).

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