Is SIN3A p.Pro417Leu (c.1250C>T) pathogenic?

SIN3A p.Pro417Leu (c.1250C>T) is classified Uncertain significance in SIN3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-03). AlphaMissense: likely benign (0.0736); Ultra-rare (popmax 0.0217%, amr); Associated with SIN3A-related intellectual disability syndrome due to a point mutation.

What condition is associated with SIN3A p.Pro417Leu (c.1250C>T)?

SIN3A p.Pro417Leu (c.1250C>T) is associated with SIN3A-related intellectual disability syndrome due to a point mutation (ClinVar).

How common is SIN3A p.Pro417Leu (c.1250C>T) in the general population?

SIN3A p.Pro417Leu (c.1250C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about SIN3A p.Pro417Leu (c.1250C>T)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

SIN3A p.Pro417Leu

c.1250C>T · rs376704049 · VCV2175766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIN3A-related intellectual disability syndrome due to a point mutation

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.44	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 9.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,842 bp · p 0.85 · regional, not allelic
Overall
CADD	23.2	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 0.0217% Admixed American · 13/59,990 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00322% 52/1,613,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,615
European (non-Finnish)	0.00314%	31,893
East Asian	0.00223%	44,886
South Asian	0.0011%	91,080

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.Pro417Leu
Coding: c.1250C>T
MANE Select: NM_001145358
dbSNP: rs376704049
Type: single nucleotide variant
Location: chr15:75409903 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 417: the 'interaction with rest' region; the 'disordered' region

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

Disease context

SIN3A-related intellectual disability syndrome due to a point mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIN3A p.Pro417= Likely benign ★ same residue
SIN3A p.Pro417Ser Likely benign ★ same residue
SIN3A p.Arg1140Ter Pathogenic ★★ same condition
SIN3A p.Arg471Ter Pathogenic ★★ same condition
SIN3A p.Arg718Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Arg935Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Arg1205His Uncertain significance ★★ same condition
SIN3A p.Gly733Arg 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-pro417leu (accessed [today's date]).

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