Is SIN3A p.His458Arg (c.1373A>G) pathogenic?

SIN3A p.His458Arg (c.1373A>G) is classified Uncertain significance in SIN3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1362); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with SIN3A p.His458Arg (c.1373A>G)?

SIN3A p.His458Arg (c.1373A>G) is associated with Inborn genetic diseases, SIN3A-related intellectual disability syndrome due to a point mutation (ClinVar).

How common is SIN3A p.His458Arg (c.1373A>G) in the general population?

SIN3A p.His458Arg (c.1373A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about SIN3A p.His458Arg (c.1373A>G)?

AlphaMissense predicts likely benign (score 0.1362) — an in-silico prediction, not a clinical call.

SIN3A p.His458Arg

c.1373A>G · rs768415150 · VCV1213737

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1362 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1362	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,842 bp · p 0.85 · regional, not allelic
Overall
CADD	23.3	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 0.00334% Admixed American · 2/59,880 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,613,108 alleles · very rare exomes 8/1,460,874 · genomes 0/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,940
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)	0.000424%	235,916

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.His458Arg
Coding: c.1373A>G
MANE Select: NM_001145358
dbSNP: rs768415150
Type: single nucleotide variant
Location: chr15:75407089 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 458: 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

Disease context

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

Also linked: SIN3A-related intellectual disability syndrome due to a point mutation

Similar variants

SIN3A p.Arg1140Ter Pathogenic ★★ same condition
SIN3A p.Arg471Ter Pathogenic ★★ same condition
SIN3A p.Arg553Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Arg718Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Arg935Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Ala242Thr Uncertain significance ★★ ⚠ same condition
SIN3A p.Arg1205His Uncertain significance ★★ same condition
SIN3A p.Arg19Trp 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-his458arg (accessed [today's date]).

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