Is SETD2 p.Lys1705Arg (c.5114A>G) pathogenic?

SETD2 p.Lys1705Arg (c.5114A>G) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.1088); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Lys1705Arg (c.5114A>G)?

SETD2 p.Lys1705Arg (c.5114A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Lys1705Arg (c.5114A>G) in the general population?

SETD2 p.Lys1705Arg (c.5114A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Lys1705Arg (c.5114A>G)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

SETD2 p.Lys1705Arg

c.5114A>G · rs771225429 · VCV2591358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 19 kb · p 4.3e-27 · regional, not allelic
Overall
CADD	25.8	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,898 alleles · very rare exomes 7/1,461,686 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000678%	147,489

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: SETD2
Protein: p.Lys1705Arg
Coding: c.5114A>G
MANE Select: NM_014159
dbSNP: rs771225429
Type: single nucleotide variant
Location: chr3:47097983 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1705: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with tuba1a' region

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg540Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn1303Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn840Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp1169Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp294Val Uncertain significance ★★ ⚠ 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/setd2-p-lys1705arg (accessed [today's date]).

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