Is SIN3A p.Ser274Pro (c.820T>C) pathogenic?

SIN3A p.Ser274Pro (c.820T>C) is classified Conflicting classifications of pathogenicity in SIN3A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1363); Very rare (popmax 0.00517%, nfe); Associated with SIN3A-related syndromic intellectual disability.

What condition is associated with SIN3A p.Ser274Pro (c.820T>C)?

SIN3A p.Ser274Pro (c.820T>C) is associated with SIN3A-related syndromic intellectual disability (ClinVar).

How common is SIN3A p.Ser274Pro (c.820T>C) in the general population?

SIN3A p.Ser274Pro (c.820T>C) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about SIN3A p.Ser274Pro (c.820T>C)?

AlphaMissense predicts likely benign (score 0.1363) — an in-silico prediction, not a clinical call.

SIN3A p.Ser274Pro

c.820T>C · VCV3318552

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1363 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIN3A-related syndromic intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1363	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -5.28	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 1,340 bp · p 0.042 · regional, not allelic
Overall
CADD	27.6	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 0.00517% European (non-Finnish) · 61/1,179,840 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00446% 72/1,613,732 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,673
European (non-Finnish)grpmax	0.00517%	19,342
Admixed American	0.00334%	29,981
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00133%	74,920

Finnish 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.Ser274Pro
Coding: c.820T>C
MANE Select: NM_001145358
Type: single nucleotide variant
Location: chr15:75411680 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.67
Residue 274: 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 syndromic intellectual disability

Similar variants

SIN3A p.Arg559Ter Pathogenic/Likely pathogenic ★★ same condition
SIN3A p.Asp975Asn Uncertain significance ★★ ⚠ same condition
SIN3A p.Gln900Ter Pathogenic ★ same condition
SIN3A p.Tyr1174Ter Likely pathogenic ★ same condition
SIN3A p.Asp939Glu Uncertain significance ★ ⚠ same condition
SIN3A p.Val200Ala Uncertain significance ★ ⚠ same condition
SIN3A p.Arg32Gln Uncertain significance ⚠ same condition
SIN3A p.Arg1134= Likely benign 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-ser274pro (accessed [today's date]).

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