Is SETDB1 p.Ala1022Val (c.3065C>T) pathogenic?

SETDB1 p.Ala1022Val (c.3065C>T) is classified Benign in SETDB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0829); Low-frequency (popmax 3.53%, sas).

How common is SETDB1 p.Ala1022Val (c.3065C>T) in the general population?

SETDB1 p.Ala1022Val (c.3065C>T) is low-frequency (popmax 3.53%, sas) (gnomAD).

What do computational predictors say about SETDB1 p.Ala1022Val (c.3065C>T)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

SETDB1 p.Ala1022Val

c.3065C>T · rs150892641 · VCV710875

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.53%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -6.14	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 2.3	GERP 0.23, phastCons 0.68
Regional constraint	o/e 0.90	unconstrained · MANE · 2,980 bp · p 0.05 · regional, not allelic
Overall
CADD	17.06	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 A1021V vs ClinVar A1022V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.53% South Asian · 3,213/91,072 alleles

Filtering AF 3.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.38%

Overall 0.425% 6,856/1,614,036 alleles · low-frequency exomes 5,237/1,461,804 · genomes 1,619/152,232 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	3.53%	28
African / African-American	3.15%	32
Remaining individualsnot grpmax-eligible	0.624%	160
Middle Eastern	0.464%	216
East Asian	0.401%	249
Ashkenazi Jewishnot grpmax-eligible	0.355%	282
Admixed American	0.343%	291
European (non-Finnish)	0.0312%	3,206

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.Ala1022Val
Coding: c.3065C>T
MANE Select: NM_001366418
dbSNP: rs150892641
Type: single nucleotide variant
Location: chr1:150961124 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.45 · 26 PDB
Residue 1021 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.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
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-ala1022val (accessed [today's date]).

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