Is SIN3A p.Pro351Ser (c.1051C>T) pathogenic?

SIN3A p.Pro351Ser (c.1051C>T) is classified Uncertain significance in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-05). AlphaMissense: likely pathogenic (0.7176); Very rare (popmax 0.0011%, sas); Associated with SIN3A-related intellectual disability syndrome due to a point mutation.

What condition is associated with SIN3A p.Pro351Ser (c.1051C>T)?

SIN3A p.Pro351Ser (c.1051C>T) is associated with SIN3A-related intellectual disability syndrome due to a point mutation (ClinVar).

How common is SIN3A p.Pro351Ser (c.1051C>T) in the general population?

SIN3A p.Pro351Ser (c.1051C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SIN3A p.Pro351Ser (c.1051C>T)?

AlphaMissense predicts likely pathogenic (score 0.7176) — an in-silico prediction, not a clinical call.

SIN3A p.Pro351Ser

c.1051C>T · rs2073605317 · VCV1098647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIN3A-related intellectual disability syndrome due to a point mutation

Computational evidence

Protein change
AlphaMissense	0.7176	likely pathogenic
REVEL	0.172	moderately benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 334 bp · p 7.7e-05 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 0.0011% South Asian · 1/91,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,714 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,034
European (non-Finnish)	0.00017%	589,971

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.Pro351Ser
Coding: c.1051C>T
MANE Select: NM_001145358
dbSNP: rs2073605317
Type: single nucleotide variant
Location: chr15:75410244 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 351: the pah 2 domain; the 'interaction with rest' 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.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
SIN3A p.Gly829Arg Uncertain significance ★★ ⚠ same condition
SIN3A p.Gly96Ser 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-pro351ser (accessed [today's date]).

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