Is SIN3A p.Arg475Gln (c.1424G>A) pathogenic?

SIN3A p.Arg475Gln (c.1424G>A) is classified Uncertain significance in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely benign (0.2945); Very rare (popmax 0.000764%, nfe).

How common is SIN3A p.Arg475Gln (c.1424G>A) in the general population?

SIN3A p.Arg475Gln (c.1424G>A) is very rare (popmax 0.000764%, nfe) (gnomAD).

What do computational predictors say about SIN3A p.Arg475Gln (c.1424G>A)?

AlphaMissense predicts likely benign (score 0.2945) — an in-silico prediction, not a clinical call.

SIN3A p.Arg475Gln

c.1424G>A · VCV3667476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2945	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 11 kb · p 3.7e-14 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000764% European (non-Finnish) · 9/1,178,004 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000617% 9/1,459,508 alleles · very rare

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: SIN3A
Protein: p.Arg475Gln
Coding: c.1424G>A
MANE Select: NM_001145358
Type: single nucleotide variant
Location: chr15:75401954 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 475: the 'interaction with sap30' region; the pah 3 domain; the 'interaction with rest' region

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

Similar variants

SIN3A p.Arg475Trp Uncertain significance ★ ⚠ same residue
SIN3A p.Arg475= Likely benign ★ same residue
SIN3A p.Arg1140Ter Pathogenic ★★ same type
SIN3A p.Arg471Ter Pathogenic ★★ same type
SIN3A p.Arg537Ter Pathogenic ★★ same type
SIN3A p.Arg553Ter Pathogenic/Likely pathogenic ★★ same type
SIN3A p.Arg559Ter Pathogenic/Likely pathogenic ★★ same type
SIN3A p.Arg718Ter Pathogenic/Likely pathogenic ★★ 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/sin3a-p-arg475gln (accessed [today's date]).

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