Is SIN3A p.Met1226Val (c.3676A>G) pathogenic?

SIN3A p.Met1226Val (c.3676A>G) is classified Uncertain significance in SIN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-08). AlphaMissense: likely benign (0.1329); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with SIN3A p.Met1226Val (c.3676A>G)?

SIN3A p.Met1226Val (c.3676A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SIN3A p.Met1226Val (c.3676A>G) in the general population?

SIN3A p.Met1226Val (c.3676A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about SIN3A p.Met1226Val (c.3676A>G)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

SIN3A p.Met1226Val

c.3676A>G · VCV3318555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -3.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 23 kb · p 1.4e-14 · regional, not allelic
Overall
CADD	22.8	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 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,731
East Asian	0.00223%	44,896
European (non-Finnish)	8.47e-05%	1,180,032

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.Met1226Val
Coding: c.3676A>G
MANE Select: NM_001145358
Type: single nucleotide variant
Location: chr15:75372125 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 1226: a UniProt-annotated variant site (in witkos)

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

Similar variants

SIN3A p.Arg553Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Ala242Thr Uncertain significance ★★ ⚠ same condition
SIN3A p.Arg19Trp Uncertain significance ★★ ⚠ same condition
SIN3A p.Arg471Gln Uncertain significance ★★ ⚠ same condition
SIN3A p.Asn1151Lys Uncertain significance ★★ ⚠ same condition
SIN3A p.Asn414Thr Uncertain significance ★★ ⚠ same condition
SIN3A p.Gln1208His Uncertain significance ★★ ⚠ same condition
SIN3A p.Gly72Ser 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-met1226val (accessed [today's date]).

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