Is SETDB1 p.Pro978Leu (c.2933C>T) pathogenic?

SETDB1 p.Pro978Leu (c.2933C>T) is classified Likely benign in SETDB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-01). AlphaMissense: likely benign (0.268); Rare (popmax 0.61%, mid).

How common is SETDB1 p.Pro978Leu (c.2933C>T) in the general population?

SETDB1 p.Pro978Leu (c.2933C>T) is rare (popmax 0.61%, mid) (gnomAD).

What do computational predictors say about SETDB1 p.Pro978Leu (c.2933C>T)?

AlphaMissense predicts likely benign (score 0.268) — an in-silico prediction, not a clinical call.

SETDB1 p.Pro978Leu

c.2933C>T · rs113110991 · VCV788766

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.268 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.61%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.268	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -5.99	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 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,980 bp · p 0.05 · regional, not allelic
Overall
CADD	23.8	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 P977L vs ClinVar P978L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.61% Middle Eastern · 37/6,062 alleles

Filtering AF 0.501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.485%

Overall 0.315% 5,078/1,613,908 alleles · rare exomes 4,718/1,461,894 · genomes 360/152,014 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.52%	28
Middle Easterngrpmax	0.61%	164
South Asian	0.54%	185
Remaining individualsnot grpmax-eligible	0.357%	280
European (non-Finnish)	0.345%	289
Admixed American	0.147%	682
Finnishnot grpmax-eligible	0.123%	810
African / African-American	0.0507%	1,972
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277

Amish 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.Pro978Leu
Coding: c.2933C>T
MANE Select: NM_001366418
dbSNP: rs113110991
Type: single nucleotide variant
Location: chr1:150960992 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.45 · 26 PDB
Residue 977 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 c.674-2A>G Uncertain significance ★ same type
SETDB1 p.Arg1244Leu Uncertain significance ★ ⚠ same type
SETDB1 p.Arg611Gln Uncertain significance ★ ⚠ same type
SETDB1 p.Asn245Asp 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-pro978leu (accessed [today's date]).

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