Is SIN3B p.Ile419= (c.1257C>T) pathogenic?

SIN3B p.Ile419= (c.1257C>T) is classified Likely benign in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-01). Rare (popmax 0.228%, nfe).

How common is SIN3B p.Ile419= (c.1257C>T) in the general population?

SIN3B p.Ile419= (c.1257C>T) is rare (popmax 0.228%, nfe) (gnomAD).

SIN3B p.Ile419=

c.1257C>T · VCV4872408

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.228%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.86	GERP -0.93, phastCons 1
Overall
CADD	8.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.228% European (non-Finnish) · 2,696/1,179,896 alleles

Filtering AF 0.221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.218%

Overall 0.214% 3,448/1,613,262 alleles · rare exomes 3,164/1,460,948 · genomes 284/152,314 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.724%	138
European (non-Finnish)grpmax	0.228%	438
Remaining individualsnot grpmax-eligible	0.189%	529
Middle Eastern	0.188%	533
South Asian	0.0945%	1,059
Admixed American	0.0784%	1,276
African / African-American	0.04%	2,501

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile419=
Coding: c.1257C>T
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16862550 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 419: the 'middle-domain' region; an α-helix; 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-ile419 (accessed [today's date]).

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