Is SIN3A p.Arg475Trp (c.1423C>T) pathogenic?

SIN3A p.Arg475Trp (c.1423C>T) is classified Uncertain significance in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely pathogenic (0.5909); Very rare (popmax 0.00223%, eas).

How common is SIN3A p.Arg475Trp (c.1423C>T) in the general population?

SIN3A p.Arg475Trp (c.1423C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SIN3A p.Arg475Trp (c.1423C>T)?

AlphaMissense predicts likely pathogenic (score 0.5909) — an in-silico prediction, not a clinical call.

SIN3A p.Arg475Trp

c.1423C>T · rs773808088 · VCV2878207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5909	likely pathogenic
REVEL	0.451	indeterminate
SaProt	LLR -12.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 11 kb · p 3.7e-14 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,850 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,611,164 alleles · very rare exomes 5/1,459,076 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,850
Admixed American	0.00167%	59,944
European (non-Finnish)	0.00034%	294,398

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.Arg475Trp
Coding: c.1423C>T
MANE Select: NM_001145358
dbSNP: rs773808088
Type: single nucleotide variant
Location: chr15:75401955 (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.Arg475Gln 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-arg475trp (accessed [today's date]).

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