Is SETDB1 p.Met792Ile (c.2376G>T) pathogenic?

SETDB1 p.Met792Ile (c.2376G>T) is classified Uncertain significance in SETDB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.8322); Very rare (popmax 8.51e-05%, nfe).

How common is SETDB1 p.Met792Ile (c.2376G>T) in the general population?

SETDB1 p.Met792Ile (c.2376G>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about SETDB1 p.Met792Ile (c.2376G>T)?

AlphaMissense predicts likely pathogenic (score 0.8322) — an in-silico prediction, not a clinical call.

SETDB1 p.Met792Ile

c.2376G>T · VCV3952904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8322	likely pathogenic
REVEL	0.539	indeterminate
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 8,259 bp · p 0.00013 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M791I vs ClinVar M792I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,088 alleles

Overall 0.000125% 2/1,598,228 alleles · very rare exomes 2/1,445,940 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,848
European (non-Finnish)grpmax	8.51e-05%	1,175,088

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: SETDB1
Protein: p.Met792Ile
Coding: c.2376G>T
MANE Select: NM_001366418
Type: single nucleotide variant
Location: chr1:150959220 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.45 · 26 PDB
Residue 791 UniProt numbering: the pre-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-met792ile (accessed [today's date]).

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