Is SIN3A p.Ser228Phe (c.683C>T) pathogenic?

SIN3A p.Ser228Phe (c.683C>T) is classified Uncertain significance in SIN3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1224); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SIN3A p.Ser228Phe (c.683C>T)?

SIN3A p.Ser228Phe (c.683C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SIN3A p.Ser228Phe (c.683C>T) in the general population?

SIN3A p.Ser228Phe (c.683C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIN3A p.Ser228Phe (c.683C>T)?

AlphaMissense predicts likely benign (score 0.1224) — an in-silico prediction, not a clinical call.

SIN3A p.Ser228Phe

c.683C>T · VCV3715671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1224 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1224	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 1,340 bp · p 0.042 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIN3A
Protein: p.Ser228Phe
Coding: c.683C>T
MANE Select: NM_001145358
Type: single nucleotide variant
Location: chr15:75412836 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 228: the 'interaction with rest' region; the 'disordered' region

Full SIN3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIN3A p.Ser228Ala Uncertain significance ★★ ⚠ same residue
SIN3A p.Arg553Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Ala242Thr Uncertain significance ★★ ⚠ same condition
SIN3A p.Arg19Trp Uncertain significance ★★ ⚠ same condition
SIN3A p.Arg471Gln Uncertain significance ★★ ⚠ same condition
SIN3A p.Asn1151Lys Uncertain significance ★★ ⚠ same condition
SIN3A p.Asn414Thr Uncertain significance ★★ ⚠ same condition
SIN3A p.Gln1208His Uncertain significance ★★ ⚠ same condition

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/sin3a-p-ser228phe (accessed [today's date]).

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