Is SIN3B p.Val577Met (c.1729G>A) pathogenic?

SIN3B p.Val577Met (c.1729G>A) is classified Uncertain significance in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3982); Very rare (popmax 6.2e-05%).

How common is SIN3B p.Val577Met (c.1729G>A) in the general population?

SIN3B p.Val577Met (c.1729G>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SIN3B p.Val577Met (c.1729G>A)?

AlphaMissense predicts ambiguous (score 0.3982) — an in-silico prediction, not a clinical call.

SIN3B p.Val577Met

c.1729G>A · VCV4165385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3982	ambiguous
REVEL	0.131	moderately benign-leaning
SaProt	LLR -8.84	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP -0.38, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 4,074 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	25.5	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 V609M vs ClinVar V577M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,010 alleles · very rare exomes 1/1,461,750 · genomes 0/152,260 · joint denominator

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.Val577Met
Coding: c.1729G>A
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16866479 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 609 UniProt numbering: an α-helix

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-val577met (accessed [today's date]).

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