Is SIN3A p.Val387Met (c.1159G>A) pathogenic?

SIN3A p.Val387Met (c.1159G>A) is classified Uncertain significance in SIN3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SIN3A p.Val387Met (c.1159G>A)?

SIN3A p.Val387Met (c.1159G>A) is associated with Inborn genetic diseases, SIN3A-related intellectual disability syndrome due to a point mutation (ClinVar).

How common is SIN3A p.Val387Met (c.1159G>A) in the general population?

SIN3A p.Val387Met (c.1159G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SIN3A p.Val387Met (c.1159G>A)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

SIN3A p.Val387Met

c.1159G>A · rs1010772312 · VCV978163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -7.73	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 0.91, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 334 bp · p 7.7e-05 · regional, not allelic
Overall
CADD	22.7	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 0.00167% Admixed American · 1/59,952 alleles

Overall 0.00031% 5/1,613,674 alleles · very rare exomes 3/1,461,550 · genomes 2/152,124 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,231
Admixed Americangrpmax	0.00167%	59,952
African / African-American	0.00134%	74,896
European (non-Finnish)	8.48e-05%	1,179,852

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val387Met
Coding: c.1159G>A
MANE Select: NM_001145358
dbSNP: rs1010772312
Type: single nucleotide variant
Location: chr15:75410136 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 387: 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-val387met (accessed [today's date]).

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