Is SIN3B p.Val348Ile (c.1042G>A) pathogenic?

SIN3B p.Val348Ile (c.1042G>A) is classified Uncertain significance in SIN3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.208); Ultra-rare (popmax 0.034%, mid).

How common is SIN3B p.Val348Ile (c.1042G>A) in the general population?

SIN3B p.Val348Ile (c.1042G>A) is ultra-rare (popmax 0.034%, mid) (gnomAD).

What do computational predictors say about SIN3B p.Val348Ile (c.1042G>A)?

AlphaMissense predicts likely benign (score 0.208) — an in-silico prediction, not a clinical call.

SIN3B p.Val348Ile

c.1042G>A · VCV3954602

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.208	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 33 kb · p 7e-09 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.034% Middle Eastern · 2/5,888 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.00329% 53/1,611,432 alleles · ultra-rare exomes 43/1,459,218 · genomes 10/152,214 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.034%	2,944
Admixed American	0.0234%	4,274
Remaining individualsnot grpmax-eligible	0.00962%	10,399
African / African-American	0.00668%	14,979
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
European (non-Finnish)	0.00204%	49,137
South Asian	0.0011%	90,870

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.Val348Ile
Coding: c.1042G>A
MANE Select: NM_001297595
Type: single nucleotide variant
Location: chr19:16854245 (GRCh38)
Gene constraint: LOEUF 0.245 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.07 · 4 PDB
Residue 348: an α-helix; the pah 3 domain; the 'interaction with ncor1' 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-val348ile (accessed [today's date]).

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