Is SETDB1 p.Ser992Thr (c.2975G>C) pathogenic?

SETDB1 p.Ser992Thr (c.2975G>C) is classified Uncertain significance in SETDB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.0612); Very rare (popmax 0.00134%, afr).

How common is SETDB1 p.Ser992Thr (c.2975G>C) in the general population?

SETDB1 p.Ser992Thr (c.2975G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about SETDB1 p.Ser992Thr (c.2975G>C)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

SETDB1 p.Ser992Thr

c.2975G>C · VCV3440261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP -0.42, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,980 bp · p 0.05 · regional, not allelic
Overall
CADD	18.81	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S991T vs ClinVar S992T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,854 alleles

Overall 6.2e-05% 1/1,612,638 alleles · very rare exomes 0/1,460,704 · genomes 1/151,934 · joint denominator

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: SETDB1
Protein: p.Ser992Thr
Coding: c.2975G>C
MANE Select: NM_001366418
Type: single nucleotide variant
Location: chr1:150961034 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.45 · 26 PDB
Residue 991 UniProt numbering: the 'disordered' region; the set domain

Full SETDB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETDB1 c.261-3T>C Likely benign ★★ same type
SETDB1 p.Ala1022Val Benign ★★ same type
SETDB1 p.Pro469= Benign ★★ same type
SETDB1 p.Pro530Leu Benign/Likely benign ★★ same type
SETDB1 p.Pro978Leu Likely benign ★★ same type
SETDB1 c.674-2A>G Uncertain significance ★ same type
SETDB1 p.Arg1244Leu Uncertain significance ★ ⚠ same type
SETDB1 p.Arg611Gln Uncertain significance ★ ⚠ same type

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/setdb1-p-ser992thr (accessed [today's date]).

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