Is SIN3B p.Pro720Ser (c.2158C>T) pathogenic?

SIN3B p.Pro720Ser (c.2158C>T) is classified Uncertain significance in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.00666%, amr).

How common is SIN3B p.Pro720Ser (c.2158C>T) in the general population?

SIN3B p.Pro720Ser (c.2158C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about SIN3B p.Pro720Ser (c.2158C>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

SIN3B p.Pro720Ser

c.2158C>T · VCV3796065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.01	GERP -3.3
Regional constraint	o/e 0.82	unconstrained · MANE · 3,350 bp · p 0.0078 · regional, not allelic
Overall
CADD	0.64	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P752S vs ClinVar P720S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000496% 8/1,613,782 alleles · very rare exomes 8/1,461,428 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
African / African-American	0.00133%	75,062
European (non-Finnish)	0.000254%	393,321

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.Pro720Ser
Coding: c.2158C>T
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16869811 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 752 UniProt numbering: the 'disordered' 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-pro720ser (accessed [today's date]).

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