Is SIN3B p.Val538= (c.1614C>T) pathogenic?

SIN3B p.Val538= (c.1614C>T) is classified Likely benign in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). Ultra-rare (popmax 0.037%, mid).

How common is SIN3B p.Val538= (c.1614C>T) in the general population?

SIN3B p.Val538= (c.1614C>T) is ultra-rare (popmax 0.037%, mid) (gnomAD).

SIN3B p.Val538=

c.1614C>T · VCV4941388

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, mid)

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 -0.32	GERP -2.5, phastCons 0.18
Overall
CADD	6.577	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.037% Middle Eastern · 2/5,410 alleles

Filtering AF 0.00657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.002% 32/1,599,802 alleles · ultra-rare exomes 28/1,447,636 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.037%	2,705
South Asian	0.00887%	11,278
East Asian	0.00675%	14,813
Remaining individualsnot grpmax-eligible	0.00647%	15,451
Admixed American	0.00505%	19,818
European (non-Finnish)	0.00103%	97,514

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.Val538=
Coding: c.1614C>T
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16865640 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 538: 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-val538 (accessed [today's date]).

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